Zentrum Für Infektionsforschung Research Center for Infectious Diseases

Zentrum für Infektionsforschung

Research Center for Infectious Diseases

Wissenschaftlicher Jahresbericht für 2005/2006 Annual Scientific Report 2005/2006

Zentrum für Infektionsforschung Research Center for Infectious Diseases

der Universität Würzburg of the University of Wuerzburg

Röntgenring 11 97070 Würzburg Germany

Phone ++49-(0)931-312064, 312575 Fax ++49-(0)931-312578 e-mail: [email protected] http://www.infektionsforschung.uni-wuerzburg.de

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3.Die Institutionen des Zentrums für Infektionsforschung

3.Institutions of the Research Center for Infectious Diseases

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3.1 Institut für Virologie und Immunbiologie, Lehrstuhl für each year. Furthermore, a variety of clinical- Virologie virological questions are being addressed. 3.1 Institute for Virology and Due to the start of allogeneic stem cell Immunobiology - Chair of transplantation at the university clinic and Virology because of new therapeutic options for the treatment of viral infections, the importance Der Lehrstuhl für Virologie im Institut für and number of viral load measurements Virologie und Immunologie betreut das and resistance tests has further increased Universitätsklinikum in allen virusdia- during the last two years. Besides the gnostischen Fragen und bekommt darüber routine testing of clinical samples, new hinaus zahlreiche Einsendungen aus ganz respiratory viruses are being studied in Deutschland und dem benachbarten Aus- cooperation with the children’s hospital of land zur Abklärung viraler Infektionen des the university clinic. The human bocavirus, Zentralen Nervensystems, eine Domäne, which was first described in 2005 by a auf die unser Lehrstuhl seit langem spezi- Swedish group, has been detected in 11% alisiert ist. Daneben werden in dieser Ab- of nasopharyngeal samples of children Axel Rethwilm teilung klinisch-virologische Fragestellun- who were hospitalised for acute respiratory 3. August 1959 gen bearbeitet, wozu z.B. die Abklärung des diseases. There were a strikingly high pathogenen Werts „neuer“ Viren gehört. number of coinfections with other respira- Neben der Virusdiagnostik ist aber, was tory viruses among the children who were die Anzahl der zum großen Teil dritmittel- positive for bocavirus DNA. Further studies finanzierten Mitarbeiter anbetrifft, die Grund- including bocavirus antibody determi- nations are currently ongoing in order to elucidate if bocavirus is a „real pathogen“ or if it is „just an innocent bystander“. Academic Education/Degrees: Besides bocavirus, the recently described 1978-1984 Study of Medicine University of Freiburg, Germany coronaviruses NL63 and HKU-1 have also 1984 Registration as M.D. been detected in the nasopharyngeal 1985 Acceptance of M.D. thesis Institute for Virology, aspirates. Additional studies have included University of Freiburg the molecular epidemiology and clinical 1985-1987 Postdoc training, German Cancer Research Center, correlation of these virus infections as well Heidelberg, Germany as the evaluation of routine diagnostic tools 1987-1989 Postdoc training Institute for Virology and Immunobiology, for their detection. University of Würzburg, Germany Tina Dörries and her team concentrate on 1989-1993 Research Associate Institute for Virology and Immunobiology, the pathogenesis of human polyomavirus University of Würzburg infections. Human polyomavirus infections 1992 "Habilitation“, Faculty of Medicine, University of Würzburg are wide spread in the world population. 1993 Assistant Professor in Virology, University of Würzburg The virus persists lifelong and is generally 1995 Associate Professor in Virology, University of Würzburg asymptomatic. However, in immunosup- 1998-2003 Full Professor and Chairman Institute for Virology, pressive states as induced by HIV-1 Medical Faculty Technical University Dresden infections, lymphoproliferative diseases or 2003 Approval as Specialist in Board of Physicians, Saxonia immunosuppressive therapies related with Microbiology and Epidemiology of Infectious Diseases transplantation, the two virus species JCV 2003 Full Professor and Co-Chairman, Institute for Virology and BKV are associated with central and Immunobiology, University of Würzburg nervous system (CNS) diseases in HIV patients, severe nephropathies after Prof. Dr. med. Axel Rethwilm lagenforschung, die in derzeit 8 Arbeits- kidney transplantation and haemorrhagic Institut für Virologie und Immunbiologie gruppen organisiert ist, der Schwerpunkt cystitis after bone marrow transplantation. Universität Würzburg des Instituts. Auch hier dominieren Erre- In each of these diseases the persistent Versbacher Str. 7 ger, die ZNS-Infektionen hervorrufen sowie infection can be activated to severe viral 97078 Würzburg Retroviren. Die einzelnen Arbeitsgruppen infections with considerable cell damage Tel.: ++49 (0)931 201-49554 stellen sich im folgenden hier vor: and symptomatic disease. Whereas in Fax: ++49 (0)931 201-49553 In the group of Benedikt Weißbrich 30-35 symptomatic disease stages no thera- [email protected] thousand clinical samples are processed peutical effect could be achieved, it is

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discussed that early diagnosis of viral On the other hand, the group tries to answer activation and therapeutic intervention the question of how great is the involvement might have a beneficial effect on the of microglia activation as an aetiological disease process. The aim is therefore to factor for HIV-induced neurodegeneration characterize accessible target cells of hu- compared to the HIV-proteins themselves man polyomavirus infections and their vi- in a cell model of microglia and neuronal ral activation state in healthy and immuno- cell types expressing the HIV-Tat protein. suppressed individuals. Lately we were Moreover, together with the group of Car- able to characterize peripheral blood cells sten Scheller, gene therapeutic ap- as target cells for JCV and BKV infection in proaches for the treatment of various general. Subpopulations affected included neuropsychiatric diseases are being lymphocytes and monocytic cell types. Risk developed. Using AAV vector-mediated group patients have a higher rate of affected expression of small interfering RNAs circulating cells, but in healthy as well as (siRNAs), the groups study knockdown of in patients at risk viral infection is latent genes involved in the pathogenesis of and only rarely single genes are ex- hereditary Alzheimer’s disease. Foamy- pressed. This suggests that peripheral virus vector-mediated expression of neu- blood cells are carrier of viral genomic rotrophic factors is being studied for the information and might be involved in the treatment of Parkinson Disease using the dissemination and enhancement of in- generation of transgenic haematopoietic fection in immunosuppressed patients. At stem cells. Moreover, the groups have present the load of infected cells appears studied latent infection of HIV in T-cells and to be correlated with the immunosup- its reactivation by CpG-oligodeoxynucleo- pressive state and thus may be a valuable tides for the development of an HIV factor for early diagnosis of polyomavirus- reactivation therapy. associated activation processes. The group of Jürgen Schneider-Schaulies The group of Eleni Koutsilieri examines investigates the interaction of surface the mechanisms by which the CNS adapts glycoproteins of morbilliviruses (e.g to injury and disease of diverse aetiology. measles and canine, seal, or dolphin Of particular concern are the interactions distemper viruses) with their species- between the various cell types in the brain specific cellular receptors. These inter- such as neurones, astrocytes and micro- actions are critically involved in the cellular glia. In one set of studies, investigations tropism of a given virus, the viral spread in on the neurobiology of HIV-dementia are the host, the ability to cross the blood-brain- being performed. Research activities in barrier and, consequently, they critically this field, besides cell biology, are exten- determine the viral pathogenesis. Besides ded to rhesus macaques and humans in a general haemorrhagic infection, these a multi-disciplinary effort that combines viruses can also cause lethal CNS di- clinical evaluation, neuroimaging, as well sease. In this context, the infection of as neurochemical, virological, immuno- endothelial and epithelial cells and a logical and neuropathological methods. directional transport of viruses or viral The molecular mechanisms, which under- protein through these cells appears to play lie exacerbation of SIV encephalopathy by an important role. The interferon-gamma- the neurotransmitter dopamine, is one of inducible enzyme indoleamine 2,3-dioxy- the main targets of the research. The group genase (IDO) could be identified in could demonstrate that drugs that are used endothelial and epithelial cells as an in the clinic to increase dopamine availa- important mediator of antiviral activity. The bility in the brain as well as drugs of abuse antiviral activity, which is most likely based dramatically accelerate SIV infection in the on tryptophane depletion, is directed brain, exacerbate neuropathological against a variety of pathogens, among them features and enhance viral load. There is herpes simplex virus (HSV-1) and measles evidence that activated microglia alter virus (MV). Antibodies against the cellular functional elements of the glutamatergic tetraspanin CD9 inhibit the canine dis- synapses in specific brain regions, render- temper virus (CDV)-induced cell fusion and ing them susceptible for excitotoxic death. possibly virus release. We found that this

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antiviral activity is mediated via the found to be severely compromised in their haemagglutinin of CDV. As a further ability to reorganise the cortical actin possibly therapeutically usable antiviral cytoskeleton as important for polarisation mechanism the aplicabilty of siRNA towards and formation of functional im- against MV was investigated. An effective munological synapses with dendritic cells inhibition of virus replication was achieved (DCs) and rather revealed an almost with siRNAs directed against transcripts complete collapse of microvillar ex- of the components of the viral replicative tensions. Moreover, again by impeding complex. Interestingly, siRNA against the PI3K activity, MV is able to regulate the activity matrix protein-mRNA stimulated the of splicing accessory proteins and thereby replication complex. Finally, the group the efficiency of alternative splicing of succeeded to establish a mouse animal cellular transcripts in T cells. A second model of a persistent MV infection of the focus is the analysis of the interaction of CNS using recombinant MV (Figure 1). MV with DCs. Entry into these cells is This model will allow a statistically con- enhanced by the ability of MV to bind to DC- firmed analysis of the role of the immune SIGN, yet they restrict late stages of the vi- system and possible therapeutic regi- ral replication cycle. To analyse these, ments in the CNS. basic studies on intracellular trafficking of In spite of the availability of an efficient live the MV M protein, which is essential for vaccine, acute MV infections are still assembly and morphogenesis, were associated with 800,000 lethal cases performed in fully permissive fibroblast cell worldwide, particularly among children in lines. developing countries. In industrialized The groups of Michael Klein and Eckhard countries, major complications include Flechsig investigate the mechanisms for pneumonia and encephalitis, which usual- the neuroinvasion of prions and the mole- ly do not take a lethal course. This, however, cular events leading to the neurode- does not apply to the subacute sclerosing generation in prion diseases. Current pan-encephalitis (SSPE), an inevitably studies address the questions whether the lethal disease, which develops with a expression of the cellular prion protein frequency of 1 per 10,000 cases of acute (PrPC) in the peripheral nervous system and measles and results from a persistent MV- the immune system are required for efficient CNS infection after a clinically silent prion transport. Furthermore, immune incubation period of several years. The therapeutic strategies are currently de- majority of measles-associated fatalities, veloped for protection against prion however, is due to a generalized transient diseases and several studies including our immunosuppression caused by MV, which own work could demonstrate that delivery favours the establishment of secondary of PrP-specific antibodies represents a infections and aggravates their clinical promising approach for prevention. More- course. MV-induced immunosuppression over, we are evaluating the underlying is characterized by a marked lymphopenia mechanisms of neurodegeneration re- and the inability of blood mononuclear cells sponsible for the destruction of the nervous to expand in response to polyclonal or system. Recently, we could show that antigen-specific stimulation in vitro. Al- oxidative stress parameters in the brain of though MV has a tropism for lympho/ prion-infected mice precede the clinical monocytic cells, the frequency of infected stages, whereas a depletion of the sero- cells is extremely low, indicating that tonin neurotransmitter transporter does not immunosuppression is a consequence of alter the susceptibility to mouse scrapie. mechanisms that are not directly related to Marc Kirschner and his team investigate the infection itself. These mechanisms are the role of soluble, trimer-stabilized and investigated in the group of Sibylle Schnei- properly cleaved HIV-1 gp140 Envelope gly- der-Schaulies. Functional consequences coproteins (Env) in vaccine development. of MV contact dependent interference with Trimeric HIV-1 Env are now being evaluated activation of the PI3/Akt kinase pathway in instead of monomeric gp120 as vaccine T cells have been a major focus of interest. antigens because they mimic more closely As a result of this inhibition, T cells were the spikes expressed on the surface of

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virions. Thus, it can be argued that Env Fluorescence Resonance Energy Trans- trimers have a more native structure than fer (FRET) as well as Bimolecular Fluo- gp120 and may be superior at raising rescence Compensation (BiFC) to detect neutralizing antibodies. In order to make substances inhibiting the Apobec-Vif trimeric Env proteins for structural and interaction and therefore preventing Apo- immunization studies we introduce an bec3G degradation. We use Apobec and engineered disulfide bond between the Vif tagged with the green fluorescent protein

gp120 and gp41ECTO subunits to stabilize (GFP) as well as its yellow (YFP) and cyan their interaction, thus allowing the ex- (CFP) derivatives to measure BiFC or FRET pression of a fully cleaved gp140 protein signals in the presence of potential anti- (SOS gp140). An additional substitution viral compounds.

(I559P) within gp41ECTO creates a more In the group of Jochen Bodem different stable, trimeric Env protein, designated as projects on primate retroviruses are SOSIP gp140. Recombinant expressed pursued. Besides studying new foamy SOSIP gp140 can be purified to homo- viruses from the New World monkey Ateles geneity by affinity as well as size exclusion and from equines the post-transcriptional chromatography. We investigate the regulation of nuclear RNA export in foamy antigenic structure and immunogenicity of viruses is investigated. Although of highly trimeric Env proteins from different HIV-1 complex genetic structure, foamy viruses subtypes as well as immunization stra- have so been regarded to lack any mecha- tegies with novel immune response nism regulating nuclear RNA export. modifiers, e.g. the Toll Like Receptor 7 Therefore these kinds of investigations are agonist Imiquimod, for optimal antigen in terms of a comparative Retrovirology of presentation in pre-clinical tests. high importance. In addition, novel mecha- In a different approach the team attempts nisms how HIV acquires resistance to anti- to develop assays to screen for alternative retroviral drugs are studied. In particular, a anti-HIV compounds that inhibit the inter- multi-resistant HIV protease has been action of the cellular antiviral protein characterized and the crystal structure is Apobec3G with the HIV-1 viral infectivity under investigation in collaboration with factor Vif. When the cytidin-deaminase part-ners in Hungary and the Czech Re- Apobec3G is packed into virions it leads to public. Furthermore, we recently obtained G to A hypermutations within the viral the first German full-length sequence of a genome, therefore rendering it inactive. The Chikungunya virus from an outbreak in Vif protein is expressed from the viral Mauritius. A German tourist imported this genome and interacts with Apobec3G virus to Würzburg when returning from the leading to its degradation by the ubiquitin island. protein degradation pathway. We are developing a screening assay based on

Figure 1: Recombinant measles virus-positive neuron in infected mouse brain.

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3.2. Institut für Virologie und siv untersucht. Ferner untersucht die Grup- Immunbiologie, Lehrstuhl für pe die differentielle Regulation des „Mas- Immunologie ter-Transkriptionsfaktors“ in B-Zellen Blimp-1. Am Lehrstuhl für Immunologie werden in vivo und in vitro Modelle der Reifung und Die Gruppen von Prof. Thomas Herrmann, Aktivierung von Lymphozyten untersucht. Dr. Thomas Kerkau, Prof. Holger Reichardt Genetisch modifizierte Maus- und Ratten- und Prof. Thomas Hünig bearbeiten ver- linien dienen der Aufklärung der Funktion schiedene Aspekte der T-Zellbiologie in einzelner molekularer Komponenten des den Tiermodellen der Ratte und Maus. Immunsystems. Monoklonale Antikörper gegen Rezeptormoleküle werden zur Ma- Prof. Herrmann und seine Mitarbeiter ar- nipulation von Immunantworten gegen beiten an der Identifizierung und funktio- Modellantigene und Krankheitserreger ein- nellen Charakterisierung „seltener“ Sub- gesetzt. populationen von T Lymphozyten, insbesondere der γ/δ T Zellen sowie der NKT In der Arbeitsgruppe von PD Dr. Ingolf Zellen, denen eine wichtige Rolle bei der Thomas Hünig Berberich wird die Regulation von Überle- unmittelbaren Infektabwehr pathogener 04. März 1950 ben bzw. programmiertem Zelltod in B-Zel- Keime zugeschrieben werden. Von beson- len untersucht. Der B-Zellantigenrezeptor derem Interesse sind dabei die Antigen- (BCR) bestimmt, ob eine B-Zelle auto- rezeptoren und Antigen-präsentierenden Moleküle auf den Zielzellen. Hier gelang die erstmalige Identifizierung des CDR2 1968-1974 Studies in Biology at the Universities of Würzburg and Heidelberg der T-Zellrezeptor-β-Kette als für die 1974 Diploma in Biology Antigenerkennung von NKT Zellen wichti- 1978 Awarded degree of Dr. of Sciences (Dr. rer. nat.) „with honors“ ger Bereich. Weiterhin wurde ein neues by the University of Würzburg nicht-polymorphes Ratten-MHC Klasse II 1979-1981 Postdoc with Dr. M. J. Bevan, MIT. Research on: Ontogeny of the Molekül mit ungewöhnlichen Superanti- T-cell repertoire in chimeric and athymic mice gen-präsentierenden Eigenschaften ent- 1981-1985 Head of a research group of the SFB 105, University of Würzurg. deckt. Die Arbeiten zur Aktivierung huma- Research on: Activation and specificity of T-cells ner Vγ9Vδ2 1984 Habilitation Immunology, University of Würzburg T Zellen durch Rezeptoren des natürlichen 1985-1990 Group Leader, Gene Center/MPI Munich. Research on: Antigen Immunsystems (NKG2D und TLR) sowie receptors and cell interaction molecules of T-lymphocytes zur Erkennung bakterieller und syntheti- since 1990 Chairman of the Department of Immunology at the Institute for scher Liganden durch den Vγ9Vδ2 T-Zell- Virology and Immunobiology, University of Würzburg. antigenrezeptor wurden fortgesetzt, wäh- Research on: Rat T-cell specificity, selection, maturation and rend die Arbeiten zur perinatalen Transmis- activation, γ/δ T-cells, IL-2/IL-2R system, CD28 sion von Toxplasma gondii abgeschlossen wurden.

reaktiv und damit schädlich ist, oder ob sie In der Gruppe von Prof. Reichardt werden für die Erkennung von „fremd“, z.B. von in- transgene Ratten- und Mausmodelle zur fektiösen Erregern, zur Verfügung steht. Analyse der intrathymischen T-Zelldif- Dementsprechend signalisiert der BCR in ferenzierung und peripheren T-Zellfunktion gerade erst entstandenen B-Zellen den entwickelt. Bisher gelang es zehn verschie- Zelltod. Rettungssignale können über das dene Linien transgener Ratten, u.a. Prof. Dr. Thomas Hünig Zelloberflächenmolekül CD40 gegeben Notch1IC-transgene sowie eGFP-trans- Institut für Virologie und Immunbiologie werden, an das Helfer-T-Zellen mit einem gene („grüne“) Tiere zu generieren und in Universität Würzburg zellständigen Liganden andocken können. verschiedenen Analysen einzusetzen. Die Versbacher Str. 7 Wichtig für die „Verarbeitung“ pro- und anti- Notch-transgenen Ratten zeigen nicht nur 97078 Würzburg apoptotische Signale in B-Zellen ist u. a. eine interessante Modifikation des T-Zell- Tel.: ++49(0)931-201-49951 das anti-apoptotische Bcl-2 Familienmit- reifungsprogramms im Thymus, sondern Fax:++49(0)931-201-49243 glied A1; das Protein wird hinsichtlich sei- entwickeln auch spontan Lymphome, die [email protected] ner Regulation und Funktionsweise inten- als Modell für entsprechende Erkrankun-

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gen des Menschen dienen können. Die Modell lösen CD8 T-Zellen eine Zerstörung eGFP-transgenen Ratten hingegen haben der Oligodendrozyten aus, was mit einem sich als wertvoll für die Analyse der Patho- Funktionsverlust von Nervenzellen und genese und Therapie von muri-nen Model- entsprechenden motorischen Störungen len der Multiplen Sklerose erwiesen. Ein einhergeht. Die Bedeutung der CD8 T-Zel- weiterer Schwerpunkt der Arbeitsgruppe ist len in der menschlichen Erkrankung ist die Funktion von Glukokortikoidrezeptoren schon länger bekannt, konnte aber bisher in der Kontrolle des Überlebens von Lym- nicht in einem geeigneten Tiermodell un- phozyten sowei der Modulation entzündli- tersucht werden. cher Prozesse.

Dr. Kerkau und seine Mitarbeiter suchen nach neuen Strategien zur Immuntherapie 3.2 Institute for Virology and der Graft-versus-host-disease (GvHD), ei- Immunobiology - Chair of ner schwerwiegenden Komplikation nach Immunology allogener Knochenmarkstransplantation. Die Immunzellen im allogenen Knochen- At the chair of immunology, in vivo and in marks-Transplantat attackieren und schä- Thomas Kerkau vitro models of lymphocyte differentiation 28. April 1959 digen die Organe des Patienten und lösen and activation are being studied. Gene- so die GvHD aus. Im Zentrum des Interes- ses einer Immuntherapie der GvHD ste- 1965-1970 Grundschule Oerlenbach/Germany hen regulatorische T-Zellen, die unter be- 1970-1978 Schönborn-Gymnasium Münnerstadt/Germany, Abitur 1978 stimmten experimentellen Bedingungen 1978-1980 National service die Aktivierung der die GvHD auslösenden University education: alloreaktiven T-Zellen unterdrücken kön- 1980-1986 Medical school at the University of Würzburg/Germany nen. Mit Hilfe neuartiger monoklonaler An- 1986 Approbation tikörper sollen die regulatorischen T-Zel- Academic career: len aktiviert und expandiert und infolgedes- Since 1987 Scientific assistant at the Institute for Virology and Immunobiology, sen die Aktivität der GvHD moduliert wer- University of Würzburg den. 1991 Medical doctorate (Dr. med.) awarded by the University of Würzburg Since 1991 Head of the laboratory of immune diagnostics at the University of Prof. Hünigs Gruppe interessiert sich für Würzburg den kostimulatorischen T-Zellrezeptor CD28 und seinen Gegenspieler, CTLA-4 tically modified mouse and rat strains are (CD152). Diese beiden Rezeptoren sind used to elucidate the function of individual entscheidend an der Regulation von T- molecular components of the immune Zellaktivierung und ihrer Unterdrückung bei system. Furthermore, monoclonal anti- Autoimmunität oder überschießenden bodies to receptor molecules are being Immunantworten beteiligt. Mit Hilfe aktivie- developed and used to manipulate the render und blockierender monoklonaler immune response against model anti- Antikörper untersuchen wir die Signal- gens and infectious agents. transduktion sowie das therapeutische Potential einer Interferenz mit der CD28- The group of PD Dr. Ingolf Berberich vermittelten Kostimulation bzw. einer focuses on the regulation of cell survival CD28-vermittelten polyklonalen T-Zell- versus programmed cell death in B-cells. aktivierung. Dabei stehen Infektions- und The B-cell antigen receptor (BCR) dictates Autoimmunitätsmodelle im Vordergrund. whether a B-cell is autoreactive or whether Von besonderer Bedeutung ist ein neues it is potentially useful in the recognition of Modell für Multiple Sklerose, bei dem das foreign invaders. Accordingly, BCR ligation Hühnereiweiß als „neo-Autoantigen“ in ei- in newly generated B-cells is interpreted nem bestimmten Zelltyp des Zentralner- as autoreactivity and hence mediates cell vensystems, den für die Isolierung der death. Rescue signals can be provided via Nervenstränge verantwortlichen Oligo- the cell surface molecule CD40, through dendrozyten, exprimiert wird. In diesem which helper T-cells can signal with a cell

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surface bound ligand. At the level of new non-polymorphic rat MHC class II with intracellular propagation of these signals, unusual superantigen-presenting pro- the analysis of the anti-apoptotic Bcl-1 perties. The work on the activation of hu- protein A1 has taken center stage in the man Vγ9Vδ2 T cells by innate immune group’s research efforts. In addition, the receptors (NKG2D and TLRs) and the group is interested in the differential recognition of bacterial and synthetic expression of the master transcription factor ligands by the Vγ9Vδ2 T-cell antigen Blimp-1 in B cells. receptor has been continued, and that on the perinatal transmission of T. gondii has The groups of Prof. Dr. Thomas Herrmann, been completed. Dr. Thomas Kerkau, Prof. Holger Reichardt and Prof. Dr. Thomas Hünig work on In the group of Prof. Reichardt, transgenic Ingolf Berberich various aspects of T-cell biology in rats and rat and mouse models are being deve- 11. Februar 1958 mice. loped for the analysis of intrathymic T-cell differentiation and function of peripheral T- cells. So far ten different transgenic rat 1977 Abitur at the Burghardt Gymnasium, Buchen strains were generated, amongst them 1979 Studies in Biology at the Universities of Würzburg Notch1IC-transgenic and eGFP-trans- 1986 Diploma in Biology genic (“green“) animals, and applied to 1990 Degree of PhD (Dr. rer. nat.) by the University of Würzburg biomedical reserach. Notch1IC-trans- 1993-1995 Postdoc with Dr. Eduard A. Clark, University of Washington, Seattle, genic rats do not only display an interesting USA. Research on: CD40 signaling in B lymphocytes modification of T-cell maturation in the since 1995 Groupleader at the Department of Immunology at the Institute for thymus, but also spontaneously develop Virology and Immunobiology, University of Würzburg. Research on: Pro T-cell lymphomas, providing a useful liferation, Differentiati on and Apoptosis of B Lymphocytes model for the study of Notch1-associated 2002 Habilitation Immunology, University of Würzburg tumors in humans. In contrast, the eGFP- transgenic rats are a valuable tool to study the pathogenesis and therapy of multiple Prof. Herrmann and his group work on sclerosis in murine models. Another focus identification and functional character- of research in the group is the function of ization of rare subsets of T-lymphocytes, glucocorticoid receptors in the control of especially γ/δ – and NKT cells, which are lymphocyte survival and the modulation of supposed to play an important role in first inflammatory processes. line defense against pathogenic microorganisms and immunoregulation. The Dr. Kerkau and his team develop novel group´s special interests are antigen strategies for the treatment of Graft-versus- receptors and antigen presenting mo- host-disease (GvHD), a frequent com- lecules on target cells. They showed that plication following allogeneic bone mar- the CDR2 region of the T-cell antigen row transplantation. GvHD is induced by receptor β-chain contributes to antigen donor-derived alloreactive T-cells attacking recognition by NKT cells and identified a tissues and organs of the patient. Re-

1977 Abitur at the Burghardt Gymnasium, Buchen 1979 Studies in Biology at the Universities of Würzburg 1986 Diploma in Biology 1990 Degree of PhD (Dr. rer. nat.) by the University of Würzburg 1993-1995 Postdoc with Dr. Eduard A. Clark, University of Washington, Seattle, USA. Research on: CD40 signaling in B lymphocytes since 1995 Groupleader at the Department of Immunology at the Institute for Virology and Immunobiology, University of Würzburg. Research on: Proliferation, Differentiation and Apoptosis of B Lymphocytes 2002 Habilitation Immunology, University of Würzburg Holger Reichardt 01. März 1969

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gulatory T cells have been shown to interfering with CD28-mediated costimu- modulate disease activity but in most lation or promoting CD28 mediated poly- cases they are not powerful enough to clonal T-cell activation. In these studies, prevent GvHD. Therefore, novel mono- we focus on models of infection and clonal antibodies which are able to activate autoimmunity. Of particular importance is regulatory T cells are now being assessed a new model of MS, in which ovalbumin is for their potential to keep GvHD in check. expressed as a neo-autoantigen in a Prof. Hünig’s group is interested in the T- certain cell type of the central nervous cell costimulatory receptor CD28 and in its system, the oligodendrocytes responsible counter-regulator, CTLA-4 (CD152). The- for the insulation of exons. In this model, se two receptors play a key role in the CD8 T-cells trigger the destruction of control of T-cell activation and its sup- oligodendrocytes, leading to a loss of pression in situations of autoimmunity or function of the neurons and corresponding excessive immune responses (hyper- motoric disturbances. While the role of sensitivity). With the help of activating and CD8 T-cells in human MS has been blocking monoclonal antibodies to CD28, suspected for a long time, so far, however, we are studying signal transduction by animal models in which their contributiion CD28, and the therapeutic potential of can be studied have been lacking.

1977 Abitur at Landschulheim am Solling, Holzminden, 1977-1985 Studies in Biology at University of Göttingen and Freie Universität Berlin 1985 Diploma in Biology. 1989 Awarded degree of PhD (Dr. rer. nat.) „with honors“ by the Freie Universität Berlin 1989-1991 Postdoc with H.R MacDonald, LICR, Epalinges/Lausanne. Research on: MHC class II binding and CD8 T cell activation by superantigens 1992-2000 Postdoc and assistant professor at the Institute for Virology and Immunobiology, University of Würzburg 1996 Habilitation in Immunology, University of Würzburg. Thomas Herrmann 2001 Associate Professor for Immunogenetics at the Institute for Virology and 24. Februar 1959 Immunobiology, University of Würzburg. Research on rat T cell repertoire and recognition of (super)antigens, γ/δ T cells and NKT cells, rat model of perinatal and congenital toxoplasmosis

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3.3 Institut für Hygiene und hausinfektionen und die Überwachung Mikrobiologie der Krankenhaushygiene zu den Auf- gaben in der Krankenversorgung. Jährlich Die Hauptaufgaben des Institut für Hy- werden ca. 85.000 diagnostische Unter- giene und Mikrobiologie sind die Labor- suchungen zu diesen Fragestellungen diagnostik von Infektionskrankheiten, die durchgeführt. Im Zentrum der Forschungs- durch Bakterien, Pilze und Parasiten aktivitäten des Instituts stehen die mole- hervorgerufen werden, die Beratung der kularen Ursachen der Entstehung von behandelnden Ärzte bei der Diagnostik, Infektionskrankheiten. Mit Methoden der Therapie und Prävention von Infektions- Molekulargenetik, Zellbiologie, Immunolo- krankheiten, die Forschung über Infek- gie und Genomforschung werden grund- tionskrankheiten und ihre Erreger, die legende Fragen der Pathogenität ver- Krankenhaushygiene und die Lehre für schiedener bakterieller und parasitärer Studierende der Medizin, Zahmedizin und Krankheitserreger bearbeitet, aber auch anderer Fachrichtungen. Im Bereich der Konzepte entwickelt, die neue Mög- Krankenversorgung verfügt das Institut lichkeiten zur Therapie und Vorbeugung zusätzlich zum vollen Spektrum der Rou- von Infektionskrankheiten eröffnen sollen. tineuntersuchungen über ein umfang- Am Institut wurde Anfang 2002 vom reiches Repertoire an molekularbio- Bundesministerium für Gesundheit das logischen Spezialuntersuchungsverfah- Nationale Referenzzentrum für Menin- Matthias Frosch ren. Ferner gehört die Erarbeitung von gokokken (NRZM) eingerichtet. Zu den 24. Februar 1960 Strategien zur Vermeidung von Kranken- Aufgaben des NRZM gehört die Identi-

1979-1986 Studies in medicine, University of Mainz 1986 MD thesis in Medical Microbiology (Prof. D. Bitter-Suermann), Institute of Medical Microbiology, Mainz 1986-1987 Post-Doc, Max-Planck Institut of Biology (Prof. T.F. Meyer), Tübingen 1987-1994 Group Leader, Institute of Medical Microbiology, Medical School Hannover 1992 Habilitation Medical Microbiology, Medical School Hannover 1994-1996 Hermann- and Lilly Schilling Professorship, Medical School Hannover since 1996 Professor (C4) of Hygiene and Microbiology, University of Würzburg Selected Awards: 1986 Heinz-Maier-Leibnitz Award (Deutsche Forschungsgemeinschaft), 1986 Tancré Award (Medical Faculty, University of Mainz) 1993 Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie) 1995 bioMerieux Diagnostik Award (Deutsche Gesellschaft f. Hygiene und Mikrobiologie) 1998 Research Award, Deutsche Gesellschaft für Hygiene und Mikrobiologie 2003 Offer of a C4-professorship for Hygiene and Medical Microbiology, University of Heidelberg since 2006 Dean ofthe MedicalFaculty, University of Würzburg Project Management: 2001- Co-ordinator „Implication of meningococcal epidemiology and population biology on public health in Europe“, EU Biomed Prof. Dr. Matthias Frosch 2001- Co-ordinator „Genomforschung an pathogenen Bakterien“ BMBF Institut für Hygiene und Microbiologie Functions in Societies: Universität Würzburg 1999-2004 Secretary of the German Society of Hygiene and Microbiology (DGHM) Josef-Schneider-Str.2 2001- Member of the scientific board of the association Berufsverband der Ärzte 97080 Würzburg für Mikrobiologie und Infektionsepidemiologie Tel.: ++49 (0)931 201-46160 2004-2006 President of the DGHM Fax:++49 (0)931 201-46445 Since 2005 President of the European Meningococcal Disease Society (EMGM) [email protected] Editorial work: www.hygiene.uni-wuerzburg.de/ since 1999 Editorial Board „International Journal of Medical Microbiology“ hwww.meningococcus.de/ since 2002 Editor „Journal of Infection“ www.echinococcus.de/ since 2004 Editorial Board „Infection and Immunity“

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fizierung und serologische bzw. mole- cell biology, immunology and genomics. kularbiologische Typisierung von Me- Furthermore, concepts are being deve- ningokokken, Beratung zum Fallma- loped to allow for novel strategies of nagement von Meningokokkenerkrankun- treatment and prevention in infectious gen und die Beratung von Gesundheits- disease. ämtern bei der epidemiologischen Unter- In 2002, the Federal Ministry of Health set suchung gehäuft auftretender Meningo- up the National Reference Center for kokkenerkrankungen. Mit diesem Aufga- Meningococci (NRZM) at the institute. benkatalog ist das Institut in eine europa- Among the tasks of the NRZM are the weite Gruppe von Referenzzentren, die identification as well as the serological „European Monitoring Group on Menin- and molecular biological typing of me- gococci“ eingebunden. Ferner ist am ningococci, and an advisory function for Institut für Hygiene und Mikrobiologie das public health departments concerning epi- Konsiliarlabor für Echinokokkose im demiological investigations of frequently Auftrag des Robert-Koch Instituts an- occurring meningococci infections. In gesiedelt. Das Institut bestimmt Serum- fulfilling these tasks, the institute forms antikörper gegen Echinococcus multi- part of a group of reference centers locularis und Echinococcus granulosus distributed all over Europe, the „European und berät zu Fragen der Diagnostik, Monitoring Group on Meningococci“. Therapie, Prävention und Epidemiologie Furthermore, by appointment of the der Echinokokkose. Robert-Koch-Institute, the consultant laboratory for echinococcosis has been set up at the institute. The respective tasks 3.3 Institute of Hygiene and comprise serological investigations on Microbiology infections caused by the cestodes Echino- coccus multilocularis and E. granulosus, The main tasks of the Institute for Hygiene and advisory functions concerning dia- and Microbiology are (i) laboratory diagnosis, therapy, prevention and epi- gnosis of infectious diseases caused by demiology of echinococcosis. bacteria, fungi and parasites; (ii) advisory functions for physicians in diagnosis, Research foci therapy and prevention of infectious diseases; (ii) basic research on infectious Comparative pathogenomics of Neisseria diseases and their causative agents; (iv) meningitidis (Christoph Schoen and Mat- hospital hygiene, and (v) teaching and thias Frosch) training for students of medicine, dentistry Neisseria meningitidis (the meningo- and several other biomedical disciplines. coccus) colonises the human nasopharynx Concerning patients care, the institute not of up to 30% of the population and most only employs the full spectrum of routine isolates from healthy carriers are con- diagnosis but also a comprehensive sidered as non-pathogenic. Only a small repertoire of special molecular techniques number of strains belonging to so called for pathogen identification and characterization. Furthermore, the development of avoidance strategies of hospital infections and hospital hygiene surveillance form part of this area of expertise. Al- together, about 85.000 diagnostic exam- inations per year are carried out in these fields of activity. Central to the research activities of the institute are the molecular mechanisms associated with infectious diseases. Basic questions on the pathogenicity of bacterial and parasitic organ-

isms are investigated by means of an array Fig.1: Immunogold-Labeling of plasminogen modern methodology of molecular biology, recruited to the surface of Neisseria meningitidis

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hypervirulent lineages are found to cause Meningococci, Institute for Hygiene and the majority of invasive diseases. A basic Microbiology, University of Würzburg, assumption is that meningococcal viru- Germany) this meningococcal pathoarray lence is genetically determined by patho- will consecutively be used for the com- genicity factors encoded in the bacterial parative genome hybridisation of genomic chromosome. However, these are at DNA from 200 representative hypervirulent present only partly understood. Therefore, meningococcal isolates currently cir- in collaboration with the teams of Dr. P culating in Germany and 100 represen- Brandt (MWG Biotech, Ebersberg, Ger- tative carriage isolates obtained recently many) and Dr. A. Goesmann (Centre for from a carriage study in Bavaria. Biotechnology, BeBiTec, University of Bie- lefeld, Germany) the whole-genome Recognition of meningococci by the hu- sequence of three non-pathogenic me- man immune system ningococcal carrier isolates were se- (Oliver Kurzai and Matthias Frosch): quenced and annotated by funding of the Focus is laid on the molecular basis of the Network of Competence PathGenoMik. interaction between N. meningitidis and Based on the publicly available genome human dendritic cells, which represent a data from the three representative hyper- major regulatory entity of human immunity. Ulrich Vogel virulent meningococcal isolates in silico Surface structures of meningococci are 27.November 1964 whole genome comparisons revealed that, tested with regard to their potential for activation of dendritic cells. Scavenger receptor A family has been identified as the major receptors mediating uptake of N. Academic career: meningitidis by dendritic cells. In close 1984-1990 Studies of Medicine at the University of Würzburg cooperation with the team of Dr. Schoen 1991-1992 AiP at the Institute for Hygiene and Microbiology Würzburg further experiments are targeted towards 1992-1996 Research Fellow at the Medical School Hannover elucidation of the molecular basis of diffe- 1996-2001 Group leader at the Institute for Hygiene and Microbiology Würzburg rent virulence in meningococcal lineages. 2000 Habilitation in Medical Microbiology 2000 Promotional award of the German Society for Hygiene and Recognition of pathogenic fungi by the im- Microbiology (DGHM) mune system since 2001 Deputy Professor at the Institute for Hygiene and Microbiology (Oliver Kurzai) (temporary engagement) Pathogenic fungi, especially Candida spp. and Aspergillus spp. are a major threat for Scientific Co-workers: immunocompromised patients. The pro- Dr. univ. Johannes Elias gnosis and putcome of these infections are Dr. med. Giuseppe Valenza bad and the immune responses evoked Dr. rer. nat. Kerstin Hubert have not yet been understood. In cooperation with the team of PD Dr. Loeffler (Medizinische Klinik und Poliklinik II) the with the exception of genes involved in activation of human granulocytes by Asper- capsule synthesis almost all other genes gillus and Candida is investigated. Surface so far considered to be virulence asso- structures responsible for recognition of ciated were also present in at least one of fungi by the innate immune system will be the non-virulent strains. Furthermore, a identified. Furthermore, the contribution of putative core patho-genome comprising different grnaulocyte effector mechanisms approximately 40 genes could be defined to inactivation of the fungi will be assessed. that is shared by all the hypervirulent strains apl. Prof. Dr. med. Ulrich Vogel and absent in the non-virulent carrier Pathogenesis and genomics of meningo- Institut für Hygiene und Microbiologie strains. Currently, on the basis of these coccal disease Josef-Schneider-Str. 2 results a meningococcal microarray is (A. Schubert-Unkmeir) 97080 Würzburg designed comprising known virulence An important feature of Neisseria menin- Tel.++49 (0)931 201-46802 associated genes and the putative patho- gitidis is its ability to invade the meninges. Fax ++49 (0)931 201-46445 genome. In close cooperation with Prof. Dr. This requires that bacteria cross the blood- [email protected] U. Vogel (National Reference Centre for cerebrospinal fluid (B-CSF) barrier, which

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is one of the tightest barriers of the body. MLVA, and PFGE for epidemiologically The major focus of our group is the defined enterococci. Ulrich Vogel is partner investigation about the molecular analysis of the European SeqNet network for of the interaction of N. meningitidis with sequence based typing (www.seqnet.org). human brain endothelial cells (HBMEC). The genetics of meningococcal capsule We have shown that meningococci spe- synthesis traditionally has been a focus of cifically invade brain endothelial cells rat- the research activities at the institute. In the her than the peripheral endothelial cells. past two years we have resolved the genetic To further improve our understanding of basis for different substrate specificities of Neisseria-host cell interactions, we have closely related meningococcal polysac- analysed gene expression profiles in charide polymerases. Furthermore, in infected HBMEC using cDNA microarrays. collaboration with Martina Mühlenhoff We are currently analysing some of these (Hannover), the function, structure and genes to determine their relevance in the population biology of polysialic acid O- specific invasion process. acetyltransferases in E. coli K1 and N. meningitidis have been studied. Infection epidemiology, bacterial capsule Finally, our group has followed two projects genetics, and complex bacterial popu- related to oral biofilms and complex Joachim Reidl lations (Ulrich Vogel, Heike Claus) bacterial populations. Firstly, we have 09. November 1961 The working group follows several re- established a meningococcal biofilm search topics related to the population model in collaboration with Søren Molin biology of meningococci and the genetics of capsular polysaccharide synthesis. In 1983-1988 Studies in biology, Diploma, University of Konstanz addition, it provides the institute with a 1992 Dr. rer. nat.; Doctoral-thesis with Prof. W. Boos, Lehrstuhl Molecular research infrastructure for typing of patho- Microbiology, University of Konstanz gens in hospital hygiene, and for the mo- 1993-1995 Post-Doc at Harvard Medical School (Prof. J.J. Mekalanos), Boston, lecular epidemiology of meningococcal USA infection in Germany, which is dealt with at 1996-2003 Junior group leader, Centre for Infectious Diseases, University of the National Reference Laboratory for Würzburg Meningococci (head: Matthias Frosch, 2001 Habilitation; Venia legendi microbiology, University of Würzburg deputy head: Ulrich Vogel). 2004 C3-Professorship for microbial physiology and cell biology, At the meningococcal reference laboratory, Institute for Hygiene and Microbiology, University of Würzburg a computer based early warning system Awards: for the detection of spatio-temporal clusters 1993-95 Post.-Doc.-Fellowship of the „Studienstiftung des Deutschen of meningococcal disease has been Volkes“ established. Precise and highly discri- 2003 Offer for a C3-professorship for molecular parodontology, University minatory DNA-sequence-based typing has of Münster been indispensable for this effort. To 2004 Offer for a professorship for microbiology, University Graz, Austria enhance laboratory surveillance in Ger- many, the collaboration with the Robert Koch-Institute and several Federal State (Lyngby, Denmark) and analysed the impact authorities has been intensified. In col- of pili and pilus associated proteins on bio- laboration with Jürgen Albert (Würzburg) film structure. The model will be used in and Dag Harmsen (Münster), a geo- future to address the yet poorly understood graphical information system has been set carrier state of meningococci. Secondly, up to facilitate the analysis of the spatio- biofilms associated with periodontal temporal distribution of specific finetypes disease have been studied by molecular (www.episcangis.org). ecology methods. A study in collaboration Prof. Dr. Joachim Reidl As methicillin-resistant Staphylococcus with the Department for Periodontology Institut für Hygiene und Microbiologie aureus and vancomycin-resistant entero- (Ulrich Schlagenhauf) has recently been Universität Würzburg cocci are of increasing importance finalized, which investigated the extent of Josef-Schneider-Str.2 for hospital hygiene, molecular typing changes to the bacterial composition 97080 Würzburg schemes have been established and induced by mechanical and antibiotic Tel. ++49 (0)931 201-46159 validated for these pathogens. Of note, we treatment in subjects with aggressive Fax ++49 (0)931 201-46445 could report of the combined use of MLST, periodontitis. [email protected]

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Host-adaptation and virulence of Haemo- philus influenzae and Vibrio cholerae (Joachim Reidl) Microbes are able to achieve high levels of adaptation in response to environmental conditions. For example, pathogenic bacteria are able to respond to changing host conditions, immune response, and antibiotic action. We are interested in investigating molecular pathogenesis and our emphasis lies on bacterial adaptation and physiology of Haemophilus influenzae and Vibrio cholerae in response to environmental and host conditions. H. influ- Fig. 2. Developing protoscolex (early stage) at enzae represents a class of bacteria, such the germinal layer of the Echinococcus multi- as Helicobacter, Streptococcus, Menigo- locularis metacestode coccus, Borrelia, Treponema, Mycoplasma etc. all of which have adapted/evolved highly colonization, persistence, and optimized specific to their host environment, i.e. the growth. Both pathogens, H. influenzae and Klaus Brehm humans. Whereas V. cholerae belongs to V. cholerae offer excellent model systems to 04. September 1964 bacteria which can be found as free living study host/pathogen interaction, since both cause significant diseases in humans (meningitis and cholera), and already 1984-1990 Studies in Biology, Diploma, University of Würzburg established animal models are available to 1995 Dr. rer. nat.; Doctoral thesis with Prof. J. Kreft and Prof. Werner investigate pathogenicity. For example, Goebel, Chair of Microbiology University of Würzburg during the past two years we unravelled the Topic: Virulence factors of Listeria monocytogenes molecular details of uptake and re-synthesis 1995-1997 Post-Doc at the Complutense University in Madrid, Spain, with pathway of the cofactor NAD in H. influenzae, Prof. Jose-Antonio Vazquez-Boland which as we showed is of critical importance Topic: Virulence gene regulation in Listeria monocytogenes for the outcome of infection in the animal 1997-2004 Research group leader at the Institute of Hygiene and model. There, we could also identify the key Microbiology, proteins, resembling a novel system of a University of Würzburg (Prof. Dr. M. Frosch); Medical Faculty coupled NAD-substrate uptake and re- Topic: Molecular biology of Echinococcus multilocularis synthesis pathway. For H. influenzae other 2004 Habilitation; Venia legendi in Medical Microbiology; important pathways have been charac- University of Würzburg terized as well in our laboratory, focusing on 2004 C3-Professorship for Medical Parasitology, Institute of Hygiene components involved in central metabolism, and Microbiology, University of Würzburg oxygen sensitivity and signal transduction Functions, Awards: regulatory pathways. For V. cholerae, we were 1995 PhD thesis ‘summa cum laude’ focusing on the role and functions of outer 1996 Awardwinner of the ‘Commemorative Foundation for Science of membrane structures, such as porins, O Lower Franconia’ antigens, capsule, and core-oligosac- since 2004 Chairman of the informal WHO working group Echinococcus basic charides lipid A, all of which play a crucial biology role in the establishment of initial coloni- since 2006 Advisory board, whole genome sequencing project Taenia solium zation. Furthermore, we characterize the Senior Scientist: molecular mechanism of the O antigen Dr. Markus Spiliotis attachment, which is con-served and of high Prof. Dr. Klaus Brehm cells in the environment, such as other relevance for most of the Gram-negative Institut für Hygiene und Mikrobiologie pathogens, for example Escherichia, pathogens. In particular, we were unravelling Universität Würzburg Yersinia, and Salmonella. Therefore, V. some biochemical pro-perties of the enzyme Josef-Schneider-Strasse 2 cholerae harbours a broad repertoire of O antigen ligase, which is the key com- 97080 Würzburg physiological attributes. Our research ponent for O antigen attachment, and which Tel.: +49(0)931-201-46168 focuses on specialized catabolic/metabolic may become a subject for inhibitor de- Fax.: +49(0)931-201-46445 pathways and cell surface-exposed struc- velopment, targeting Gram-negative and LPS [email protected] tures, which facilitate optimal adaptation, producing bacteria.

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Developmental biology of the fox-tapeworm organisms. In particular, we showed that Echinococcus multilocularis and molecular three host-derived hormones, insulin, EGF, host-parasite interactions in alveolar and BMP2, directly interact with corres- echinococcosis (Klaus Brehm) ponding surface receptors of the parasite (host insulin binds to the insulin-receptor- Parasitic helminths infect more than 2 like Echinococcus tyrosine kinase EmIR; billion people world-wide. They are con- BMP2 functionally interacts with the TGF- sidered promising therapeutics against b-receptor-like kinase EmTR1) and stimu- autoimmune-diseases and allergies, and, late corresponding intracellular signalling from the view of developmental biology, they cascades in E. multilocularis (host EGF display several highly interesting traits. activates the parasite’s MAP kinase Despite all this, parasitic helminths are a cascade). These data indicate that para- neglected group of organisms when sitic helminths, contrasting to bacteria, compared to other infectious agents such protozoa or fungi, utilize their phylogenetic as bacteria, protozoa or fungi. Their cell relationship with vertebrates to persist biological peculiarities are only rudimentarily within the host. Based on primary cell investigated and little is known concerning cultivation systems for Echinococcus which the molecular basis of the complex host- we have recently developed, promising helminth interactions during an infection. approaches to genetically manipulate the We are using one of these organisms, the parasite are currently under way, which will Marianne Abele-Horn fox-tapeworm Echinococcus multilocularis, be important for future studies concerning 27. November 1947 as a model system to address fundamen- the molecular basis of host-helminth tal questions regarding organ-tropism and interactions. host-induced parasite development in Academic career: helminthic infections. On the one hand, we 1969 – 1973 Studies of Pharmacy, Universities of Erlangen and Tübingen approach a closer genetic characterization 1973 – 1979 Studies of Medicine, University of Freiburg and Medical School of the parasite by means of several EST- Hannover and whole genome sequencing projects, 1977 PhD thesis in Pharmacy, Institute of Pharmacology, which also addresses basic questions University of Freiburg concerning the worm-specific processing 1980 – 1993 Resident, Institute of Microbiology, Krankenhaus München- mechanism of mRNA trans-splicing. By Schwabing molecular genetic and biochemical ap- 1984 – 1986 Resident, Department of Internal Medicine, Klinikum Rechts der proaches, we could show that E. multi- Isar, München locularis employs several signal trans- 1994 – 1998 Consultant, Max von Pettenkofer-Institute, University München duction systems (insulin-, EGF, FGF-, TGF- since 1999 Consultant, Institute of Hygiene and Microbiology, b-signalling) which are closely related to the University Würzburg respective signalling systems of vertebrates 2000 Habilitation in Medical Microbiology, University Würzburg both on the structural and the functional level. 2005 Infectious Disease Specialist (DGI) The most important tools of our investi- Selected Awards: gations are several in vitro cultivation 1993 Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie) systems which mimic the in vivo infection 2000 Lectureship Award (International Organization for Mycoplasmology) situation and by which the development of 2000 Research Award (Deutsche Gesellschaft für Pädiatrische Infektiologie) the parasitic larvae within the liver of host Editoral Work: organisms can be investigated under 1998 – 2000 Co-editor „Infection“ laboratory conditions. Using these culti- Scientific Co-workers: vation systems, we already showed that Dr. med. Dennis Tappe soluble cytokines and hormones which are Dr. med. Giuseppe Valenza present in the host liver during an infection Prof. Dr. med. Dr. rer. nat. (e.g. insulin, EGF, BMP2) do have crucial Marianne Abele-Horn effects on the development and differen- Institut für Hygiene und Mikrobiologie tiation of parasitic larvae. Recently, we Josef-Schneider-Straße 2 demonstrated that the effect of these host 97080 Würzburg hormones on the parasite is mediated by Phone ++49 931 201 46941 the evolutionary conserved signalling Fax ++49 (0)931 201-46445 systems that are shared between both [email protected]

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1990-1999 Studies of Physics and Medicine at the Ludwig-Maximilian-University, Munich,and Georg-August-University, Göttingen 1999-2001 Medical Assistant (AiP) at the Clinic for General and Vascular Surgery, Klinikum Bremen Mitte, and at the Clinic for Internal Medicine II, University Hospital Würzburg 2000 M.D. thesis in Molecular Medical Mycology (Prof. R. Rüchel), Institute for Medical Microbiology, Georg-August-University, Göttingen 2004 PhD in Microbiology (Prof. W. Goebel), Department of Microbiology, Christoph Schoen Julius-Maximilians-University, Würzburg 15. Februar 1970 2002-2003 Postgraduate degree in Bioinformatics, Ruprecht-Karls-University, Heidelberg Dr. rer. nat. 2004- Postdoc with Prof. Dr. M. Frosch, Institute of Hygiene and Microbiology, Dr. med. Christoph U. Schoen University of Würzburg Institut für Hygiene und Mikrobiologie 2006- Junior group leader University of Würzburg Fellowships/Awards: Josef-Schneider-Str. 2 1991-1996 Student fellowship of the Friedrich-Naumann-Stiftung 97080 Würzburg 2000-2004 MD/PhD stipend of the BMBF Tel.: +49 931 201 46901 Senior Scientist: Fax:+49 931 201 46445 Dr. Biju Joseph [email protected]

Heike Claus 24.Juni 1961 Academic career: Dr. rer. nat. Heike Claus 1989-1995 Studies of Biochemistry at the University of Hannover Institut für Hygiene und Mikrobiologie 1995-2000 PhD thesis at the Medical School Hannover and the Josef-Schneider-Str. 2 University of Würzburg 97080 Würzburg since 2000 Research Fellow at the Institute for Hygiene and Microbiology, Tel.: +49 931 201 46036 University of Würzburg Fax: +49 931 201 46445 [email protected]

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1989-1996 Studies of Medicine at the Medical School Hannover 1997-1998 AiP at the Institute for Medical Microbiology, University of Mainz 1999-2002 Research Fellow at the Institute for Hygiene and Microbiology, University of Würzburg since 2002 Group leader at the Institute for Hygiene and Microbiology, University of Würzburg 2006 Specialist for Microbiology, Virology and Infection Epidemiology Alexandra (Bayerische Landesärztekammer) Schubert-Unkmeir Research Topics: 12. November 1969 Molecular basis of host-pathogen interaction in meningococcal meningitis Project Management: Dr.med. Alexandra Schubert-Unkmeir 2003-2005 Interaction of Neisseria meningitidis with cells of the human blood brain Institut für Hygiene und Mikrobiologie barrier Schwerpunktprogramm SPP1130 „Infektionen des Endothels“ University of Würzburg since 2004 Interaction von Meningokokken und Gruppe B-Streptokokken mit Josef-Schneider-Str. 2 kardiovaskulären Zellen: Molekulare Mechanismen und pathophysio- 97080 Würzburg logische Bedeutung (IZKF University of Würzburg, A33) Tel.: +49 931 201 46901 Fax: +49 931 201 46445 [email protected]

1994-2001 study in medicine, University of Würzburg 2002 MD thesis in Medical Microbiology (Prof. M. Frosch), Institute of Hygiene & Medical Microbiology, Würzburg 2002- Post-Doc, Institute of Hygiene & Medical Microbiology, Würzburg 2006- Group leader IZKF A50 „Interaction of pathogenic fungi with human neutrophils“ Oliver Kurzai 2007- Group leader SFB 479 „In vivo relevant expression of virulence genes of 23. August 1975 N. meningitidis“ Awards: 1994-2001 Student Fellowship of the Studienstiftung des Deutschen Volkes Dr. med. Oliver Kurzai 2002 DGHM Becton-Dickinson Dissertation Award IInstitut für Hygiene und Mikrobiologie 2003 Dissertation Award of the Medical Faculty Würzburg Josef-Schneider-Strasse 2 2003 Science Award of the Unterfränkische Gedenkjahrstiftung 97080 Würzburg. 2005 Travel Grant (Instand e.V.) Tel.: +49 931 201 46905 Senior Scientist: Fax: +49 931 201 46445 Dr. Corinna Schmitt [email protected]

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3.4 Lehrstuhl für Mikrobiologie beteiligt sind, und die Regulation der Theodor-Boveri-Institut, Expression dieser Faktoren; (c) die Biozentrum metabolischen Voraussetzungen von L. monocytogenes, die es diesem Bakterium Der Lehrstuhl für Mikrobiologie hat eine ermöglichen sich nach seinem Vor- lange Tradition in der Charakterisierung dringen in das Cytosol der eukaryon- der molekularen Grundlagen der Wech- tischen Zell dort zu vermehren; d) Reak- selwirkung zwischen Bakterien und ihren tionen der Wirtszelle nach Invasion durch eukaryontischen Wirten. Der Schwerpunkt die Bakterien. Bei diesen Untersuch- liegt dabei auf humanpathogenen Kei- ungen spielen moderne genomische men, wobei verschiedene Modellorga- Techniken wie Transkriptom- und Proteo- nismen untersucht werden. Als Bespiel für mcharakterisierungen eine besondere fakultativ intrazelluläre Erreger werden in Rolle, da mittlerweile die Genomse- den Arbeitsgruppen von Werner Goebel quenzen mehrerer Listeria Arten (L. und Jürgen Kreft Listerien benutzt. Listeria innocua, L. ivanovii, L. seeligeri und L. wel- monocytogenes kann durch kontaminierte shimeri), sowie verschiedener Serotypen Nahrungsmittel aufgenommen werden von L. monocytogenes vorliegen. und in immunsupprimierten Patienten Viele der in diesen Projekten erhaltenen schwere Krankheitsbilder mit einer hohen Erkenntnisse werden in der Arbeitsgruppe Mortalitätsrate verursachen, wie z.B. von Werner Goebel dazu benutzt, neu- Sepsis oder Hirnhautentzündung. Eine artige Lebendimpfstoffe gegen verschie- besondere Eigenschaft dieses Erregers dene Krankheitserreger bzw. therapeu- ist zudem, dass er intrauterin von der tische Impfstoffe gegen bestimmte Krebs- Mutter auf den Fötus übertragen werden erkrankungen zu entwickeln. Der An- kann, was zum Abort oder zu einer be- satzpunkt dieser Untersuchungen liegt Werner Goebel sonders schweren Erkrankung (Granulo- darin begründet, dass L. monocytogenes 19. September 1939 matosis infantiseptica) des neugebo- in das Cytosol einer eukaryontischen Zelle vordringen kann. Es wurden apathogene Academic Curriculum: Varianten dieser Bakterien erzeugt, die 1963-63 Studies of Chemistry at the University of Tübingen zwar noch in das Cytosol vordringen, sich 1965-65 PhD Thesis (supervisor Prof. Dr. F. Lingens) dort aber nicht mehr vermehren können. Diese Bakterien kodieren für ein Enzym, 1966-69 Research Fellow with Prof. Helinski, University of California das die Lyse der Bakterien verursacht, San Diego/ La Jolla sobald sie sich im Cytosols der Wirtszelle 1969-71 Research Assistant at the Institute for Microbiologiy University of befinden. Enthalten die Bakterien z.B. Hohenheim (Prof. Lingens) einen DNA-Impfstoff, wird dieser durch die 1971 Habilitation in Microbiology and Biochemistry at the University of Lyse der Bakterien im Cytosol freigesetzt Hohenheim und kann dort im günstigen Fall die 1972-75 Head of the Genetics Department at the GBF in Stöckheim, gewünschte Immunreaktion auslösen. concomitantly H3-Professor for Biochemistry at the University of Weitere fakultativ intrazelluläre Erreger, die Braunschweig am Lehrstuhl bearbeitet werden, sind since 1975 Chair of Microbiology at the University of Würzburg verschiedene pathogene Enterobakterien Selected Functions and Awards: wie Salmonellen und enteroinvasive E. 1983 Robert-Koch Award coli (EIEC) Stämme. Auch in diesen Projekten stehen ähnlich wie bei den 1984 ASM Lecture Award oben genannten Listerien Fragen zur 2006 Emil-von-Behring Award Aufnahme der Bakterien in ihre eu- Member of several academies such as the Leopoldina and the American karyontischen Wirtszellen und ihrer Fäh- Academy for Microbiology igkeit, sich in diesen Zellen zu vermehren, Prof. Dr. Werner Goebel im Mittelpunkt. renen Kindes führt. Die Arbeiten bein- Als Modellorganismen für extrazelluläre Lehrstuhl für Mikrobiologie halten folgende Schwerpunkte: (a) Ein- Erreger werden am Lehrstuhl Bakterien Biozentrum der Universität Würzburg blicke in die Evolution von Virulenz- der Gattungen Helicobacter und Bordetella Am Hubland eigenschaften, die einige harmlose untersucht. Helicobacter pylori hat sich auf 97074 Würzburg Umweltbakterien dieses Genus wie L. den menschlichen Magen als Habitat Germany seeligeri oder L. innocua vom pathogenen spezialisiert und verursacht verschiedene Tel: +49 (0)931 - 888 - 4400 Keim L. monocytogenes unterscheiden; Erkrankungen, darunter Magengeschwü- Fax: +49 (0)931 - 888 - 4402 (b) das Verständnis der bakteriellen re. Eine lange anhaltende Infektion mit [email protected] Faktoren, die am Virulenzgeschehen diesem Erreger kann aber auch zu

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Magenkrebs oder zum MALT-(mucosa- Versuchstieren. Während der Koloni- assoziiertes Lymphgewebe)-Lymphom sierung der Tumoren, die im Rückgang führen. In der Arbeitsgruppe von Dagmar und der Eliminierung des Tumors führt, Beier werden schwerpunktmäßig Fragen wird die Konzentration an Zytokinen, der Wahrnehmung von Umweltreizen und Chemokinen und Wachstumsfaktoren der daran gekoppelten Regulation gene- parallel zur Rekrutierung und Aktivierung tischer Programme in H. pylori und eng von Immunzellen gemessen. Dabei wer- verwandten Bakterien, sowie die Re- den RT-PCR, Mikroarrays und immuno- gulation der bakteriellen Chemotaxis un- histochemische Methoden eingesetzt. Die tersucht. Der Genus Bordetella beinhaltet Arbeitsgruppe erwartet, den Beitrag von eine Reihe human- oder tierpathogener humanen Tumorzellen und von Maus- Arten. In der Arbeitsgruppe von Roy Gross stroma bestimmen zu können, der die werden die molekularen Mechanismen bakteriolytische und onkolytische Eli- der Evolution von Virulenzeigenschaften minierung der soliden Tumoren und in diesem Genus untersucht, die aus- Metastasen durch das wirtseigene (auto- gehend von Umweltorganismen wie B. loge) Immunsystem ermöglicht. petrii zur Entstehung des Keuchhu- Eliminierung der soliden Tumoren und stenerregers B. pertussis geführt haben. Metastasen durch das wirtseigene (auto- Da mittlerweile auch für dieses Genus die loge) Immunsystem ermöglicht. genomischen Sequenzen einer ganzen Reihe von Arten ermittelt wurden, kommen auch hier moderne genomische Methoden 3.4 Chair of Microbiology, zum Einsatz. Einen zweiten Schwerpunkt Theodor-Boveri-Institute, bilden, wie auch bei der Charakterisierung von Helicobacter, Untersuchungen zur Biocenter Wahrnehmung von Umweltreizen durch diese Bakterien, die dadurch die Ex- The Chair of Microbiology has a long pression ihrer Virulenzgene umwelt- tradition in the characterization of the bedingt regulieren können. molecular basis of the interaction of Im Gegensatz zu den vorher genannten bacteria and their eukaryotic hosts. The Projekten wird in der Arbeitsguppe von Roy main emphasis lies on those bacteria that Gross eine symbiontische Beziehung von are pathogens for man. As an example of obligat intrazellulären Bakterien des facultatively intracellular agents, in the Genus Blochmannia mit ihren Wirtstieren, groups of Werner Goebel and Jürgen Kreft, Ameisen der Gattung Camponotus, un- bacteria of the genus Listeria are in- tersucht. Die kürzlich fertiggestellte Ge- vestigated. Listeria monocytogenes can be Selected References: nomsequenz von Blochmannia floridanus transmitted by contaminated food and can - Eisenreich, W., Slaghuis, J., Lauptiz, zeigt auf, dass diese Bakterien eng mit cause severe diseases in immunocom- R., Bussemer, J., Stritzker, J., Schwarz, pathogenen Enterobakterien verwandt promised patients such as meningitis and C., Schwarz, R., Dandekar, T., sind, dass sie eines der kleinsten bisher septicemia. A feature of high relevance is Goebel , W. and Bacher, A. (2006) bekannten Genome haben und lässt the fact that the agent can be transmitted 13C isotopolouge perturbation studies zudem vermuten, dass sie ihren Wirts- intrauterine from the mother to the fetus of Listeria monocytogenes carbon tieren bestimmte Nährstoffe wie z.B. which may cause either abortion or a metabolism and its modulation by the essentielle Aminosäuren zuführen. severe systemic disease (granuloma- virulence regulator PrfA. Proc Natl Acad In der Arbeitsgruppe von Aladar Szalay tosis infantiseptica) in the newborn. The Sci USA 103: 21040-2045. wird der Einsatz von attenuierten patho- project is focused on the following points: - Joseph, B., Przybilla, K., Stuhler, C., genen Mikroorganismen als Lebend- (a) insights in the evolution of the patho- Schauer, K., Slaghuis ,J., Fuchs, T.M. impfstoffe untersucht. Die Beobachtung, genic properties, which distinguishes and Goebel, W. (2006) Identifcation of dass intravenös applizierte Bakterien, harmless environmental species such as Listeria monocytgenes genes con- Vaccinia Virus und Säugerzellen, in solide L. seeligeri and L. innocua from the tributing to intracellular regplation by Tumoren und Metastasen eindringen, pathogenic species L. monocytogenes; (b) expression profiling and mutant screen- replizieren und persistieren, öffnet neue the characterization of the bacterial factors ing. J Bacteriol 188: 556-568. Wege für Mikroben-basierte kombinierte relevant for virulence and the regulation of - Schoen, C., Kolb-Mäurer, A., Geginat, Tumordiagnostik und Therapie. Zusätzlich expression of these virulence factors; (c) G., Löffler, D., Bergmann, B., Stritzker, zu Schwachlicht (Lumineszenz) Em- the metabolic prerequisites of L. mono- J., Szalay, A.A., Pilgrim, S. and mission durch genetisch veränderte cytogenes which enable this bac-terium Goebel, W. (2005) Bacterial delivery Luziferase Gene tragen die Lebend- to multiply within the cytosolic com- of functional messenger RNA to vektoren Gene zur simultanen Detektion partment of eukaryotic cells; d) reactions mammalian cells. Cell Microbiol 7: 709- und Therapie von Tumoren in lebenden of the host cell on invasion by these 724.

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bacteria, which can reach the cytosol of As model organisms for extracellular the host cell where they multiply. Important pathogens, bacteria of the genera Helico- tools for these studies are modern ge- bacter and Bordetella are investigated. nome based technologies such as the Helicobacter pylori has specialized to the characterization of the transcriptome and human stomach as its unique habitat and proteome of these bacteria, since in the can cause different kinds of disease such meantime the genomic sequences of as ulcers. Long lasting infections with several Listeria species (L. innocua, L. these bacteria can also generate stomach Fig. 1: ivanovii, L. seeligeri, and L. welshimeri) cancer or the MALT (mucosa associated Listeria monocytogenes as vehicle for DNA vaccines. The genetic information and even of several serotypes of L. lympoid tisse) lymphoma. In the group of coding for a relevant antigen is trans- monocytogenes are available. Dagmar Beier the molecular basis of the ported via bactofection into an antigen Several of the insights gained by these perception of environmental signals such presenting cell (1) und is liberated in projects are used by the group of Werner as acid and the changes in the genetic the cytosol (2). Production of the antigen by the host cell (3) and presentation on Goebel to develop novel types of live programs of H. pylori and closely related the cell surface (4), thus triggering an vaccines against various pathogens or bacteria as a response of changes in immune response against the antigen. therapeutic vaccines against certain types these signals are investigated. Moreover, the regulation of the chemotactic response of H. pylori is analysed. The genus Bordetella comprises a series of human or animal pathogens. In the group of Roy Gross the molecular mechanisms leading to the evolution of virulence properties in these bacteria are investigated, which led from environmental organisms such as Bordetella petrii to the emergence of B. pertussis, the etiological agent of whooping cough. Since several genomic sequences of various Bordetella species are available since recently, modern genomic techniques are applied for these investigations. The second project involves the characterization of signal transduction systems of the various Bordetella species, which are involved in the coordinated regulation of virulence of cancer. The basis of these inves- gene expression according to changing Selected references: tigations is the fact that L. monoytogenes environmental conditions. -Dominguez-Bernal, G., Müller-Altrock, is able to reach the cytoplasm of its host Contrary to all previous projects, in the S., Gonzalez-Zorn, B., et al. (2006) A cell. Variants of L. monocytogenes have group of Roy Gross a mutualistic re- spontaneous genomic deletion in been constructed which are not anymore lationship between obligate intracellular Listeria ivanovii identifies LIPI-2, a pathogenic. These variants still are able bacteria of the genus Blochmannia and species-specific pathogenicity island to reach the cytoplasm of the host cell, but their animal hosts, ants of the genus encoding sphingomyelinase and nu- they have lost their ability to multiply Camponotus, is investigated. The ge- merous internalins. Mol Microbiol therein. The bacteria code for an enzyme nome sequence of Blochmannia flori- 59:415-432. which causes the lysis of the bacteria danus was recently established and - Gopal, S., Borovok, I., Ofer, A., Yanku, upon their entrance in the cytosol of the revealed that this bacterium is closely M., Cohen, G., Goebel, W., Kreft, J., host cell. If such bacteria contain a DNA- related to pathogenic Enterobacteriaceae, and Aharonowitz, Y. (2005) A multi- vaccine it will be released into the cytosol that it has one of the smallest genomes domain fusion protein in Listeria and may therefore cause the desired so far described, and that the bacteria very monocytogenes catalyzes the two immune response. likely supply the host organism with certain primary activities for glutathione Additional facultative intracellular patho- nutrients such as essential amino acids. biosynthesis. J Bacteriol 187:3839- gens worked with at the Chair of Micro- In the group of Aladar Szalay the use of 3847. biology comprise various Enterobac- attenuated pathogens as live vectors is - Hain, T., Steinweg, C., Kuenne, C.T., teriaceae among which there are Salmo- investigated. The discovery that intra- Billion, A., et al. (2006) Whole-genome nella and enteroinvasive E. coli (EIEC) venously injected bacteria, Vaccinia virus sequence of Listeria welshimeri reveals strains. In these projects similar questions and mammalian cells, enter, replicate and common steps in genome reduction are delt with as in the case of the Listeriae persist in solid tumours and metastases with Listeria innocua as compared to such as the invasion strategies of these opens the way for microorganism based Listeria monocytogenes. J Bacteriol bacteria and their ability to multiply within combined tumour diagnostics and thera- 188:7405-7415. the eukaryotic host cell. py. In addition to low light (luminescence)

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emission by engineered luciferase genes, Using this combined approach, the wor- the live vectors do carry different thera- king group focuses on the following peutic genes for simultaneous detection aspects: and therapy of tumours in live animal - Low molecular weight protein-tyrosine models. During tumour colonization, phosphatases (LMW-PTPs). For other which results in tumor regression and pathogens it has been shown that such elimination, the presence of cytokines, enzymes are involved in the regulation of chemokines and growth factors is mon- virulence. Infection experiments with L. itored in parallel with the recruitment and monocytogenes mutants deleted for LMW- activation of immune cells using RT PCR, PTP genes showed a defect in invasive- microarrays and immuno-histochemical ness. In transcription studies, using whole methods. The group expects to dissect the genome microarrays, we could identify contribution of the human tumour cells and several candidate genes responsible for that of the mouse stroma to bacteriolytic these biological effects. Gene-specific and oncolytic elimination of solid tumours analyses using quantitative reverse- Jürgen Kreft and metastases by the host (autologous) transcription PCR („real time RT-PCR“) 27. September 1945 immune system. corroborated a pleiotropic effect of the

Scientific Career: 3.4.1 Post-genomic analysis of Listeria 1967-1969 Studies of Biology at the TH Stuttgart virulence (Jürgen Kreft) 1970-1972 Studies of Biology at the University of Hohenheim 1977 PhD Thesis at the University of Stuttgart Listeriae are ubiquitous, very robust gram- 1977 Research Fellow and Group leader at the Chair of Microbiology, positive bacteria. The two species L. University of Würzburg monocytogenes and L. ivanovii can cause, in humans and animals, the rare but often 1984 Habilitation in Microbiology at the University of Würzburg fatal disease listeriosis. From their natural 1992 Appointment for Professorship at the Chair of Microbiology, habitat (decaying plant matter in soil) the University of Würzburg bacteria easily contaminate food and thus Fellowships and Awards: can reach their eukaryotic hosts. There 1987 Deputy Chairman of the Diploma Committee for Biology they cross the intestinal barrier, multiply 1998 Award of the „Seeliger-Stiftung“ with in the spleen and liver and eventually 2005 Gay-Lussac/Humboldt Award may even breach the blood-brain and placentar barrier, causing e.g. meningo- Listeria LMW-PTPs on the transcription Prof. Dr. rer. nat. Jürgen Kreft encephalitis or a severe systemic infection and also the translation of numerous Biozentrum - of the unborn. L. monocytogenes has genes. Among them are genes for invasion Lehrstuhl für Mikrobiologie evolved very sophisticated mechanisms factors of the internalin family, an important to invade its primary eukaryotic host cells, motility gene and genes for stress pro- Am Hubland to multiply therein and to spread to other teins. The influence of the phosphatases 97074 Würzburg cells. It is regarded as a model organism on the multiplication and the metabolism Tel.: +49 (0)931 888 4419 for the important group of facultative of Listeria will be investigated further, as Fax: +49 (0)931 888 4402 intracellular bacterial pathogens, which well as the biochemical characteristics of [email protected] includes e.g. the causative agent of these enzymes. tuberculosis. In 2001, with a significant contribution from the Würzburg Listeria research group, the complete genome sequences of one isolate of L. monocytogenes and its close, but harmless relative L. innocua, have been published. Further Listeria genomes have been completed by the Würzburg-based Patho- GenoMik competence network. The genome sequence of the environmental species L. welshimeri has been published recently. This opened an avenue for the identification of novel virulence factors, using first comparative genome analysis and then precisely targeted genetic and Fig.2: Scanning electron micrograph of Listeria invading biochemical experiments. Caco-2 enterocytes

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- Glutathione synthetase. Glutathione hemagglutinin (FHA), the per-tactin (PRN) (gamma-glutamyl-cysteine-glycine, GSH) and the fimbriae, and several toxins such is an important, redox-active thiol in many as the adenylate cyclase toxin (CYA) and cells. The original annotation of the L. the pertussis toxin (PTX) that is except- monocytogenes genome classified the ionally produced only by B. pertussis. The GSH biosynthetic pathway as being expression of these factors is regulated incomplete, missing the gene for the according to environmental stimuli such second enzyme, glutathione synthetase as temperature. The two-component (GshB). In a collaboration with the Tel Aviv system BvgAS is required for this environ- University (Prof. Y. Aharonowitz) we could mental regulation of virulence factors and characterize a novel bifunctional enzyme, consists of the transmembrane histidine GshF, which combines all the necessary kinase BvgS and the cytoplasmic trans- catalytic activities in one polypeptide. Such cription factor BvgA. BvgS is the sensor an unusual enzyme seems to be present protein that transforms the environmental also in other bacteria. We have generated stimuli into a cellular signal via several mutations in other genes of the so called phosphorylation events, which finally lead thiol-redox metabolic network (TRMN) of to activation of BvgA. The BvgA protein then L. monocytogenes. The comprehensive interacts with the promoters of the viru- Roy Gross genetic, biochemical and functional lence genes and induces their trans- 11. Oktober 1956 analysis of the TRMN, performed together cription. with the Israeli partner, will be the focus of A major research interest regards the mo- our future research. lecular characterization of the regulatory mechanisms which control virulence gene expression. The BvgAS system belongs Scientific career: to a small subfamily of unorthodox two- 1976-1981 Studies of Biology at the Eberhard-Karls-University of Tübingen component systems, which are charac- 1981-1982 Diploma Thesis under the Supervision of Prof. Dr. V. Braun terized by a more complex domain struc- 1982 Diploma (Master of Science) ture than the classical systems. In contrast 1982-1985 PhD Thesis under Supervision of Prof. Dr. V. Braun to classical sensor proteins the BvgS 1985-1989 Postdoctoral Research Fellow at the Sclavo protein contains additional C-terminal Research Center in Siena, Italy signalling domains. A complex multistep 1990-1991 Research Scientist at the Pasteur Institut, Paris, with Prof. Dr. A. phosphorelay between alternating histi- Ullmann dine and aspartate residues occurs in 1991 Research Assistant (C1) at the Chair of Microbiology, University of those unorthodox systems. Mutation and Würzburg with Prof. Dr. W. Goebel complementation analyses demonstrated that in contrast to other unorthodox sensor 1993 Qualified as University Lecturer in Microbiology (Habilitation) proteins these additional domains are 1994 Assistant Professor at the Chair of Microbiology, University of essential for BvgS function indicating that Würzburg the phosphorelay is obligate in this 1997 Appointment as an Associate Professor for Microbiology (C3) at the system. By the comparison of the struc- University of Würzburg turally related BvgAS and EvgAS (from E. Fellowships and awards coli) two-component systems we could Various fellowships from the European Union, EMBO, HFSPO demonstrate the importance of the C- 1990 Young Investigator Award of the DGHM terminal domains of the unorthodox since 2004 Member of the Editorial Board of the Journal „Microbes and Infection“ sensor proteins for the specificity of the since 2006 Member of the Editorial Board of the Journal „BioSpektrum“ signal transduction process and the activation of the BvgA and EvgA effector proteins. By a detailed structure-function 3.4.2 Virulence properties and their analysis based on a combination of evolution in the genus Bordetella (Roy biophysical, biochemical and genetic Gross) approaches, we could demonstrate that Prof. Dr. rer. nat. Roy Gross the transcription factors BvgA and EvgA are The genus Bordetella consists of several Biozentrum - dimers even in the non phosphorylated highly related pathogenic species in- form. Moreover, our investigations have Lehrstuhl für Mikrobiologie cluding the etiological agent of whooping provided evidence that the BvgS and EvgS Am Hubland cough, B. pertussis, and several animal histidine kinases are responsive to the 97074 Würzburg pathogens such as B. bronchiseptica. oxidation status of the electron carrier Tel.: +49 (0)931- 888 -4403 These bacteria produce many virulence ubiquinone (Q-8) in addition to the pre- Fax: +49 (0)931- 888 -4402 related factors, among which there are viously known environmental signals such [email protected] several adhesins such as the filamentous as temperature. This indicates that the

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virulence regulon of the pathogenic fimbriae, FHA and other putative virulence Selected References: Bordetellae is linked with the energy state factors. -Beier, D., and Gross, R. (2006) of the bacteria. Regulation of bacterial virulence by The second focus of this project regards 3.4.3 Intracellular bacterial endosymbionts two-component systems. Curr Opin evolutionary processes which led to the of insects (Roy Gross) Microbiol 9: 1-10. expression of different pathogenic pro- -Stübs, D., Fuchs, T.M., Schneider, B., perties in the various Bordetella species. More than a 100 years ago F. Blochmann Bosserhoff, A., and Gross, R. (2005) We compare the classical Bordetella described the presence of intracellular Identification and regulation of cold species B. pertussis, B. parapertussis and bacteria in midgut and ovarial cells of ants inducible factors of Bordetella bron- B. bronchiseptica with new Bordetella of the genus Camponotus. Recently we chiseptica. Microbiology 151: 1895- species which have been isolated from started to investigate this symbiotic 1909. patients only recently such as B. holmesii, relationship on the molecular level. -Zientz, E., Beyaert, I., Gross, R. and B. hinzii and B. trematum. Of special Cloning and analysis of the 16S rRNA Feldhaar, H. (2006) Relevance of the interest is a new organism, B. petrii, genes of the symbiotic bacteria of fourteen endosymbiosis of Blochmannia flori- isolated from a river sediment, which is Camponotus species collected in Europe danus and carpenter ants at different an environmental isolate most closely and Southern- and Northern America stages of the life cycle of the host. Appl related to members of the genus Bor- allowed their classification within the Env Microbiol 72: 6027-6033. detella. The project involves the com- gamma-subclass of the Proteobacteria. parison of species specific putative The ant symbionts are more closely virulence properties such as invasion related to each other than to any other mechanisms in epithelial cells, intra- known organism and have recently been cellular survival in professional phago- proposed to be members of a novel cytes, resistance mechanisms against genus: Candidatus Blochmannia (gen. stress inducing agents and host specific nov.). The closest relatives are endo- antimicrobial compounds (e.g. defen- symbiotic bacteria of the tsetse fly (Wig- sins). In addition, we identify and charac- glesworthia spp.) and of aphids (Buchnera terize genetic differences between the aphidicola) which together form a huge different species which provide insights cluster of symbiotic organisms and have in the molecular mechanisms of evolution a common ancestor with the Entero- within this group of important pathogens. bacteriaceae. In parallel to the phylo- Recently, we have determined the ge- genetic analysis of the bacteria we per- nomic sequence of the environmental formed a related analysis with the host organism B. petrii. The comparison of this animals characterizing their mitochondrial sequence with those of the mammalian cytochome oxidase subunit I gene se- pathogens allow us to get insights in the quences. Interestingly, the phylogenetic evolution of virulence properties in the trees of the ants and their symbionts are genus Bordetella. First results indicate that congruent indicating a long lasting co- all species including the environmental speciation of these organisms. In fact, the isolate B. petrii code for orthologous bacteria appear to be transmitted ma- genes encoding the BvgAS system, ternally, as in situ hybridization with sym-

Fig. 3: Porposed metabolic interactions of Blochmannia floridanus and its host Camponotus floridanus deduced from the genome of B. floridanus

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biont specific oligonucleotides unequi- which are involved in transcriptional vocally showed the bacteria in the midgut regulation. Interestingly, the few two- and in the ovaries to be identical. The component proteins of H. pylori show characterization of the symbiont migration unexpected properties. Two of the five during embryogenesis by in situ hybridi- response regulators are essential for cell zation revealed an early association of the growth, while the three histidine kinase bacteria with endodermal tissues. The genes can be deleted without effect on the genomic sequence of Blochmannia has recently been determined. This sequence growth phenotype. In addition, the se- confirms the close relationship of Bloch- quence of the N-terminal receiver doma- mannia with the Enterobacteriaceae. ins of two-response regulators differs from Similar to other bacteriocyte symbionts, the consensus sequence at usually highly Blochmannia has a strongly reduced conserved positions suggesting a mode genome size of about 705 kb. The aim of of activation of these regulator proteins this study is to investigate the molecular which differs from the well-known two- basis of this symbiosis, adaptation component paradigm. All two-component mechanisms of the partners to each other proteins are required for colonization in a and to understand the biological sig- mouse model of infection. In case of the nificance of this interspecies interaction. ArsRS two-component system this ob- servation can be explained by the fact that ArsRS in response to acidic pH regulates 3.4.4 Two-component signal transduction the expression of genes involved in the in Helicobacter pylori (Dagmar Beier) pronounced acid resistance of H. pylori. The ArsRS-regulated genes include the Helicobacter pylori colonizes the human urease gene cluster encoding the major gastric mucosa and is the aetiologic agent acid-resistance determinant of H. pylori of chronic gastritis and peptic ulcer disease. which is essential for host colonization. The In addition, infection with H. pylori is a risk aim of the project is the functional char- factor for the development of gastric acterization of the two-component proteins malignancies like adenocar-cinoma and of H. pylori as well as the identification and MALT lymphoma. Probably as a con- characterization of target genes which are sequence of its tight adaptation to the hu- under control of the two-component man stomach as its exclusive niche H. systems. Of particular interest are essen- pylori contains only a very restricted tial regulated genes which might be targets repertoire of transcriptional regulators. The for the development of new therapeutic genome of H. pylori encodes three hi- stratagies against H. pylori infections. stidine kinases and five response re- A complex two-component system parti- Dagmar Beier gulators belonging to the family of two- cipates also in chemotactic signalling. 31. März 1964 component signal transduction system Interestingly, the composition of the

Scientific career: 1983-1989 Studies of Chemistry at the University of Würzburg 1992 PhD thesis at the University of Würzburg 1992-1995 Postdoctoral fellow at the Chair of Microbiology, University of Würzburg 1995-1998 Postdoctoral fellow at the Immunobiological Research Institute Siena (IRIS) PD Dr. rer. nat. Dagmar Beier 2002 Habilitation Biozentrum - Lehrstuhl für Mikrobiologie Positions, fellowships: Am Hubland 1998 group leader 97074 Würzburg 1992-1995 Postdoctoral fellowship, Deutsche Forschungsgemeinschaft (DFG) Tel.: ++49 (0)931- 888-4421 1995-2000 AIDS-fellowship, Federal Ministry of Education and Research Fax: ++49 (0)931- 888-4402 2000-2002 Research fellowship (Habilitations-Stipendium), DFG [email protected]

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Fig.4: Two-component systems of H. pylori involved in transcriptional regulation

chemotactic apparatus of H. pylori differs Selected references: markedly from the well-studied entero- -Pflock, M., Finsterer, N., Joseph, B., Mollen- bacterial system and shows some simi- kopf, H., Meyer, T.F., and Beier, D. (2006) larity to the chemotactic system of Sino- Characterization of the ArsRS regulon of rhizobium meliloti. We are focussing on Helicobacter pylori involved in acid adaptation. J Bacteriol 188: 3449-3462. the characterization of the complex phos- -Pflock, M., Kennard, S., Delany, I., Scarlato, photransfer reactions between the dif- V., and Beier, D. (2005) Acid-induced activation ferent two-component proteins which of the urease promoters is mediated directly control chemotactic signalling in H. pylori. by the ArsRS two-component system of Helicobacter pylori. Infect Immun 73: 6437-6445. -Schär, J., Sickmann, A., and Beier, D. (2005) Phosphorylation-independent activity of atypical response regulators of Helicobacter pylori. J Bacteriol 187: 3100-3109.

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3.5 Institut für Molekulare auch Gastwissenschaftler aus dem In- und Infektionsbiologie Ausland. Die Arbeit wird vor allem über Dritt- mittel der Deutschen Forschungsge- Das Institut für Molekulare Infektions- sellschaft (DFG), des Bundesministeriums biologie wurde im Jahre 1993 als interdis- für Bildung und Forschung (BMBF), der Eu- ziplinäre Einrichtung an der Medizinischen ropäischen Union (EU) und anderer Fakultät der Universität Würzburg gegrün- Förderungsorganisationen finanziert. Mit- det. Da der Lehrstuhlinhaber gleichzeitig arbeiter des Instituts für Molekulare Mitglied der Medizinischen und Biologi- Infektionsbiologie sind in verantwortlichen schen Fakultät ist, wurde das Institut schon Positionen in den Selbstverwaltungsorga- bei seiner Gründung mit dem Ziel ange- nisationen der Universität, in Fachgesell- legt, eine „Scharnierstelle“ zwischen den schaften und forschungsfördernden Insti- beiden Fakultäten zu sein. Es bestehen tutionen des In- und Auslandes tätig. Be- auch wissenschaftliche Beziehungen zu sonders intensive Beziehungen bestehen den Fakultäten für Chemie und Pharmazie zu den Nachwuchsgruppen des Zentrums und für Physik. Die am Institut bearbeite- für Infektionsforschung, die organisato- ten Projekte befassen sich mit molekula- risch mit dem Institut für Molekulare ren Aspekten von Infektionsprozessen. Infektionsbiologie assoziiert sind und mit Weiterhin wird Infektionsbiologie in der dem ein enger Austausch auf wissen- Lehre vertreten. Dabei werden Lehr- schaftlichen Gebiet erfolgt. Jörg Hinrich Hacker veranstaltungen vor allem für Biologie- und 13. Februar 1952 für Biomedizinstudenten, aber auch für Stu- denten der Medizin und der Zahnmedizin 3.5 Institute for Molecular angeboten. Die Graduiertenausbildung Infection Biology spielt eine große Rolle beim Lehrengage- ment der Mitglieder des Institutes, die sich auch an der Etablierung der „Graduate School of Life Sciences“ der Universität The Institute for Molecular Infection Biology Würzburg beteiligt haben. was founded in 1993 as an interdis- Die Arbeitsgruppen des Instituts für Mole- ciplinary institution at the Medical Faculty kulare Infektionsbiologie befassen sich mit of the University of Würzburg. As the den vielfältigen, molekularen Aspekten von chairman has also been a member of the Infektionen, die durch Bakterien, Parasiten Faculty of Biology, one of the first objectives und Pilzen hervorgerufen werden. In der of the institute was to represent a link Arbeitsgruppe „Molekulare Parasitologie between these two faculties. Furthermore, und Infektionsimmunologie“ (Leiterin H. an intensive scientific and organizational Moll) werden insbesondere die Interaktio- relation has been build to the faculties of nen zwischen parasitären Infektions- pharmacy, chemistry and physics. The erregern und dem Immunsystem analy- research of the institute aims to elucidate siert. Die Arbeitsgruppe „Molekulare Myko- fundamental aspects of infection pro- logie“ (Leiter: J. Morschhäuser) befaßt sich cesses. Additionally, the members of the mit den Krankheitsprozessen bei Pilz- institute present biological problems of infektionen. Die bakteriologischen Arbeits- infectious diseases in lectures, seminars gruppen untersuchen ein breites Spektrum and practical courses in particular to the Prof. Dr. Dr. h. c. mult. Jörg Hacker an Erregern, wobei sowohl Enterobak- students of the Biology department, but Institut für Molekulare Infektionsbiologie terien, Gram-positive Bakterien wie Staphy- also to a certain extent to medical and den- Röntgenring 11 lokokken und Enterokokken als auch tal students. As the education of graduate 97070 Würzburg Legionellen in die Studien mit einbezogen students is thereby one of the main Tel.: ++49-931-312575 werden. Es werden sowohl die Interaktio- focuses, the Institute for Molecular Infection Fax: ++49-931-312578 nen zwischen den Erregern und den Wirts- Biology has been involved in establishing [email protected] zellen als auch die dynamischen Prozes- the „Graduate School of Life Siences“ at www.infektionsforschung.uni- se der Erregervariabilität beleuchtet. the University of Würzburg. wuerzburg.de Am Institut für Molekulare Infektionsbiologie (curriculum vitae of Jörg Hacker, sind ca. 50 Personen tätig, neben Wissen- The groups at the Institute for Molecular see page 6) schaftlern, Doktoranden, Diplomanden, Infection Biology study several molecular

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aspects of infections that are caused by bacteria, parasites and fungi. The research group ‘Molecular Parasitology and In- fectious Immunology’ (headed by Heidrun Moll) is particularly interested in interactions between parasitic pathogens and the immune system. The research group ‘Molecular Mycology’ (headed by Joachim Morschhäuser) investigates disease processes of fungal infections. The bac- teriological research groups study a broad spectrum of pathogens including enterobacteria, legionellae, Gram-positive bacteria such as staphylococci and enterococci. Both interactions between pathogens and host cells and the dynamic processes in pathogen variability are subjects of interest of these groups. The Institute for Molecular Infection Biology employs ca. 50 persons that comprise scientists, graduate students, under- graduates and visiting researchers from Germany and from abroad. The work is primarily financed by funds from the Deut- sche Forschungsgemeinschaft (DFG), the Federal Ministry of Education and Re- search (BMBF), the European Union (EU) and several other grant organizations. Members of the institute take responsibility in positions of the University’s

Fig. 1: Electronmicroscopy of Enterobacteria

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3.5.1 Immunological and cell biological results show that newly formed phago- studies on the pathogenicity of Leishmania somes in DC rapidly develop into late parasites (Heidrun Moll) endosomal compartments. However, the small GTPase Rab7, which regulates late a)The biogenesis of Leishmania-harbor- fusion processes, was found only in PV of ing vacuoles in dendritic cells mature DC and was absent in immature In mammalian hosts, Leishmania para- DC, suggesting an arrest of their PV sites are obligatory intracellular and invade biogenesis at the stage of late endosomes. macrophages and dendritic cells (DC) Indeed, fusion assays with endocytic where they reside in endocytic organelles tracers demonstrated that the fusion activity termed parasitophorous vacuoles (PV). of L. major-harboring PV towards lyso- Most of the present knowledge of the somes is higher in mature DC than in im- characteristics of PV harboring Leishma- mature DC. The inhibition of PV-lysosome nia is derived from studies with infected fusion in DC is dependent upon the viability macrophages. Since DC play a key role in and life cycle stage of the parasite, because host resistance against leishmaniasis, live promastigotes blocked the fusion there is a need to understand the properties almost completely, whereas killed orga- and biogenesis of PV in Leishmania- nisms and amastigotes induced a con- infected DC. Therefore, we determined the siderable level of fusion activity. The acquisition of endosomal and lysosomal differences in the fusion competence of molecules by Leishmania major-con- immature and mature DC may be relevant taining compartments in DC at different for their distinct functional activities in the Heidrun Moll maturation stages, using fluorescence uptake, transport and presentation of 30. August 1957 labeling and confocal microscopy. The parasite antigens.

Education and Academic Appointments: 1976-1981 Studies in Biology, University of Konstanz (Diploma) 1982-1985 Doctoral Studies at the Max-Planck-Institute of Immunobiology, Freiburg 1985 Ph.D., University of Konstanz 1986-1988 Postdoctoral fellow, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia 1988-1993 Senior scientist, Institute of Clinical Microbiology and Immunology, University of Erlangen 1993 Habilitation (Immunology), Medical Faculty of the University of Erlangen 1993-1998 Group leader, Research Center for Infectious Diseases, University of Würzburg 1995- Professor and Head of the Infection Immunology Unit, Institute for Molecular Infection Biology, University of Würzburg 2004- Vice President of the University of Würzburg Selected Awards, Committees, Editorial Boards: 1986-1988 Fellowship of the DFG (German Research Foundation) 2000 Siebold Nagasaki Medical Award 2001- German Society of Parasitology, Board member 2003- German Society of Immunology, Board member 2003- Editorial Board member „Infection and Immunity“ 2004- Editorial Board member „European Journal of Cell Biology“ 2004- Editorial Board member „Current Immunology Reviews“ Prof. Dr. Heidrun Moll 2004- Member of Senate Committee and Grants Committee on Research Training Institut für Molekulare Infektionsbiologie Groups („Senatsausschuss und Bewilligungsausschuss für die Röntgenring 11 Graduiertenkollegs“), German Research Foundation D-97070 Würzburg 2005- German Society of Parasitology, Vice President Germany Senior Scientists / Postdoctoral fellows: Tel.: ++49 (0)931-31 2627 Prof. Dr. Alicia Ponte-Sucre (since 2004) Fax: ++49 (0)931-31 2578 Dr. Marcela Fajardo-Moser (since 2004) [email protected] Dr. Dr. Katharina Remer (since 2005)

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b) Identification and characterization of effects of NIQs and CP inhibitors against leishmanicidal compounds Leishmania major and its major host cells, Chemotherapy of leishmaniasis is mainly macrophages and dendritic cells. Treat- based on antimony compounds. However, ment of L. major promastigotes, the their toxicity causes serious side effects. extracellular parasite form, with specific Moreover, resistance to antimonials is fre- NIQs and CP inhibitors resulted in dose- quent and can reach 50-65 % of the treated dependent inhibition of parasite growth

cases in some areas of the world. Second- with IC50 values in the low micromolar line drugs are also toxic and require close range. Both types of compounds decreased clinical control. Finally, current anti- the infection rate of peritoneal macro- leishmanial treatments remain extremely phages at concentrations that were 8- to expensive for countries in which the 500-fold lower and, thus, had an even more disease is endemic. These issues em- potent effect on intracellular Leishmania phasize the urgent need for affordable al- amastigotes. CP inhibitors were less toxic ternative drugs against leishmaniasis. against host cells than NIQs. Furthermore, CP inhibitors, but not NIQs, were able to Schemes to develop novel leishmanicidal modulate the cytokine secretion and nitric drugs include the analysis of naturally oxide production by host macrophages. Our occurring plant-derived compounds, such results suggest that the intracellular form as naphthylisoquinoline alkaloids (NIQs), of the parasite is more sensitive to the which were shown to be interesting drug compounds and demonstrate that NIQs Selected references: candidates for the use against Leishma- and CP inhibitors are promising candi- - Körner, U., Fuss, V., Steigerwald, J., nia. Another promising strategy is the dates for further investigation of their and Moll, H. (2006) The biogenesis of targeting of parasite cysteine proteases leishmanicidal activity. Leishmania major-harboring vacuoles (CPs) which are essential for their growth, in murine dendritic cells. Infect Immun differentiation and pathogenicity. To identify 74: 1305-1312. new leishmanicidal compounds for poten- - Ponte-Sucre, A., Faber, J.H., Gulder, tial clinical use, we compared the cytotoxic T., Kajahn, I., Pedersen, S.E.H., Schult- heis, M., Bringmann, G., and Moll, H. (2007) Activity of naphthyl-isoquinoline Lamp1 L. major Merge alkaloids and synthetic analogs against Leishmania major. Antimicrob Agents Chemother, 51: 188-194. - Ponte-Sucre, A., Vicik, R., Schultheis, M., Schirmeister, T., and Moll, H. (2006) Aziridine-2,3-dicarboxylates: peptido- mimetic cysteine protease inhibitors with antileishmanial activity. Antimicrob Agents Chemother 50: 2439-2447. - Moll, H. (2006) Dendritic cells in leishmaniasis: Regulators of immunity Fig. 2: Endosomal compartments in DC harbor Leishmania parasites. DC infected for and tools for new immune intervention one hour with L. major that had been prestained with 5-chloromethylfluoresceindiacetat strategies. In: Handbook of Dendritic (CMFDA, green) were subjected to intracellular staining for Lamp1, a marker of late endosomes/lysosomes, using a phycoerythrin-labeled antibody. The localization of Lamp1 Cells – Biology, Diseases and Thera- (red, left) and L. major parasites (green, center) was analyzed by confocal microscopy. A pies, M. B. Lutz, A. Steinkasserer and parasite residing in a parasitophorous vacuole that also contains Lamp1 is indicated by N. Romani (eds.), Wiley-VCH, Wein- μ arrows (merge, right). Bar: 5 m. heim, Germany, pp. 669-691.

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3.5.2 Biology and Pathogenicity of Candida albicans (Joachim Morschhäuser) sion, and antifungal drug resistance in C. albicans. We are studying the role of Infections by opportunistic fungi have ammonium permeases in the induction of become a major medical problem in the filamentous growth in response to nitrogen past decades. The yeast Candida albicans starvation. By comparing C. albicans and is a harmless commensal in most healthy the closely related, but less pathogenic people, but it can also cause mucosal as species C. dubliniensis we identified a well as life-threatening systemic infections, central regulator of chlamydospore for- especially in immunocompromised pa- mation, a developmental programme tients. A variety of virulence-associated found only in these two species (see Fig. characteristics contribute to the capacity of 3). In a project of the SFB 479, we in- C. albicans to adapt to and multiply in many vestigate how the switching between the different host niches. These include the normal yeast form and a mating-com- metabolic adaptation to the nutritional petent, so-called opaque cell form is requirements in various host niches regulated in certain C. albicans strains. In encountered during an infection, the addition, we are analyzing the regulatory environmentally regulated transition be- networks controlling the expression of efflux tween the budding yeast form and several pumps that are responsible for the filamentous forms, and the generation of development of antimycotic drug re- Joachim Morschhäuser genetic variants which are better adapted sistance. Another aim, which is the topic of 30. März 1963 to permanent alterations in the host a project within the SFB 630, is the environment, like antifungal drug-resistant identification and functional analysis of strains. substances that either directly inhibit growth Our group is characterizing the signals and of C. albicans or block the virulence or signal transduction pathways controlling resistance mechanisms of this fungus in morphogenesis, virulence gene expres- order to develop novel antifungal agents.

Academic career: 1983-1989 Studies of Biology in Frankfurt/Main and Würzburg 1989-1993 Dissertation at the University of Würzburg 1993-1997 Project leader at the Research Center for Infectious Diseases in Würzburg 1997-2000 Junior group leader at the Research Center for Infectious Diseases in Würzburg 1999 Habilitation 2001-2002 Heisenberg fellow of the DFG at the Institute for Molecular Infection Biology, University of Würzburg 2002-2003 Heisenberg fellow of the DFG at the Max-von-Pettenkofer Institute in München 2004- Professor (C3) at the Institute for Molecular Infection Biology, University of Würzburg Fellowships and awards: 1991-1993 Doctoral thesis fellowship of the „Studienstiftung des deutschen Volkes“ 1994 Thesis of award of the „Vereinigung für Allgemeine und Angewandte Prof. Dr. rer. nat. Mikrobiologie“ (VAAM) Joachim Morschhäuser 2000 Promotion award of the „Deutsche Gesellschaft für Hygiene und Institut für Molekulare Infektionsbiologie Mikrobiologie“ (DGHM) Röntgenring 11 2001-2003 Heisenberg fellowship of the „Deutsche Forschungsgemeinschaft“ D-97070 Würzburg 2001 Research promotion award of the „Deutschsprachige Mykologische Tel.: ++49 (0)931-312152 Gesellschaft“ (DMykG) Fax: ++49 (0)931-312578 2002 Robert Koch promotion award of the Bergstadt Clausthal-Zellerfeld [email protected] Senior scientist: wuerzburg.de Dr. Peter Staib

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C. albicans wild-type C. albicans nrglΔ C. dubliniensis wild-type

Fig. 3: Chlamydospore formation in C. albicans and C. dubliniensis. This developmental programme is differentially regulated in the two species. While both produce chlamydospores on rice agar, only C. dubliniensis forms chlamydospores on Staib agar, because it downregulates the NRG1 repressor. C. albicans continues to express NRG1 under these conditions and grows only in the yeast form, but inactivation of the NRG1 gene results in chlamydospore formation also in C. albicans. Shown are phase contrast (top panels) and scanning electron micrographs (bottom panels) of a C. albicans wild-type strain (left), a C. albicans nrg1 mutant (middle) and a C. dubliniensis wild- type strain (right) grown on Staib agar. The arrows point to the large chlamydospores formed at the tips of pseudohyphae.

Selected references: - Staib, P., and Morschhäuser, J. (2005) Differential expression of the NRG1 repressor controls species-specific regulation of chlamydospore development in Candida albicans and Candida dubliniensis. Mol Microbiol 55: 637-652. - Biswas, K., and Morschhäuser, J. (2005) The Mep2p ammonium permease controls nitrogen starvation-induced filamentous growth in Candida albicans. Mol Microbiol 56: 649-669. - Reuß, O., and Morschhäuser, J. (2006) A family of oligopeptide transporters is required for growth of Candida albicans on proteins. Mol Microbiol 60: 795-812.

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3.5.3 Analysis of virulence mechanisms in evolution of pathogenic bacteria. For this and genomic diversity of extraintestinal pathogenic and non-pathogenic Escheri- purpose, we use the uropathogenic E. coli Selected references: chia coli (Ulrich Dobrindt) strain 536 as well as the non-pathogenic -Hochhut, B., Wilde, C., Balling, G., E. coli strain Nissle 1917 as model Middendorf, B., Dobrindt, U., Brzusz- Pathogenic enterobacteria cause several organisms to analyze the genome or- kiewicz, E., Gottschalk, G., Carniel, E., diseases in humans and animals. Extra- ganization, distribution of virulence- and Hacker, J. (2006) Role of patho- intestinal pathogenic E. coli are involved associated genes as well as their function genicity island-associated integrases in urinary tract infections, newborn menin- and expression. The complete genome in the genome plasticity of uro- gitis and sepsis. Some E. coli variants sequence of strain 536 is included into pathogenic Escherichia coli strain 536. cause severe systemic infections of comparative analyses of complete ge- Mol Microbiol 61:584-595. animals. Among different members of the nome sequences of other pathogenic and -Nougayrède, J.-P., Homburg, S., Taieb, F., Boury, M., Brzuszkiewicz, E., Enterobacteriaceae and especially among non-pathogenic E. coli strains and other Gottschalk, G., Buchrieser, C., Hacker, different E. coli isolates, the genome sizes enterobacteria in order to identify factors J., Dobrindt, and U., Oswald, E. (2006) vary significantly. DNA acquisition by which may be responsible for the different Escherichia coli induces DNA double horizontal gene transfer as well as loss of diseases observed. The unstability of PAIs strand breaks in eukaryotic cells. genetic information contribute to the and the role of PAI-encoded bacteriophage Science 313:848-851. genetic diversity among Enterobacteria- integrases for PAI deletion is studied in -Brzuszkiewicz, E., Brüggemann, H., ceae and are important mechanisms detail as well as regulatory networks Liesegang, H., Emmerth, M., Öl- involved in genome optimization of these involved in virulence gene regulation. schläger, T., Nagy, G., Albermann, K., organisms. Furthermore, we aim at the functional Wagner, C., Buchrieser, C., Emõdy, L., The group studies processes involved in characterization of novel virulence-asso- Gottschalk, G., Hacker, J., and Do- genetic diversity and genome optimization ciated genes in extraintestinal pathogenic brindt, U. (2006) Comparative genomic of pathogenic and commensal entero- E. coli. The group also focusses on factors analysis of extraintestinal pathogenic Escherichia coli strains reveals how to bacteria. Analysis of the underlying and mechanisms contributing to multi- become an uropathogen. Proc Natl mechanisms will provide us with a better cellular behaviour and biofilm formation Acad Sci USA 103:12879-12884. understanding of the processes involved of extraintestinal pathogenic E. coli.

Fig. 4: Mechanisms involved in bacterial genome optimization.

Scientific career: 1989-1995 Study of Biology in Göttingen Ulrich Dobrindt 1999 PhD thesis at the Institute for Molecular Infection Biology, 07. Juli 1970 University of Würzburg 1999 Research assistant at the Institute for Molecular Infection Biology AR Dr. rer. nat. Ulrich Dobrindt Functions, distinctions: Institut für Molekulare Infektionsbiologie 1996-1998 PhD scholarship of the Boehringer Ingelheim Fonds Röntgenring 11 2001- Group leader (E. coli Pathogenomics) 97070 Würzburg 2004 Promotion award (Förderpreis) of the German Society for Hygiene and Tel.: ++49 (0)931 312155 Microbiology (Deutsche Gesellschaft für Hygiene und Mikrobiologie) Fax: ++49 (0)931 312578 Scientific coworkers: [email protected] Dr. Caroline Wilde

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3.5.4 Bacterial Adhesins and Invasins-Early carbohydrates for the ability to interfere with steps in bacterial infection and counter- bacterial adherence to and/or invasion into measures (Tobias Ölschläger) host cells of several E. coli pathotypes, Selected references: An early essential step in the establish- Salmonella and Shigella. In vitro host cell - Alpert, C., Engst, W., Gühler, A., ment of bacterial infections is adhesion to models employed are human urinary tract Oelschlaeger, T.A., and Blaut, M. (2005) host surfaces mediated by fimbriae/pili or and gut epithelial cell lines and cryo- Bacterial response to eukaryotic cells: afimbrial adhesins. Expression of these sections of human gut biopsies. In ad-dition analysis of differentially expressed proteins using nano liquid chromato- bacterial surface structures interferes with the mouse model was used. graphy-electrospray ionization tandem mechanical action of the host aimed at Besides mechanisms of molecular patho- mass spectrometry. J Chromatography removing bacteria. Therefore, adherence genicity the machinery of probiotics to 1082: 25-32. counteract these is investigated. For that is a common property of bacteria able to - Schultz, M., Watzl, S., Oelschlaeger, colonize or infect macroorganisms e.g purpose the Escherichia coli strain Nissle T.A., Rath, H.C., Göttl, C., Lehn, N., humans. In addition, several pathogenic 1917 (EcN) was chosen as a model for Schölmerich, J., and Linde, H.-J. bacteria are not only restricted to host probiotic bacteria, because its efficacy was (2005) Green fluorescent protein for surfaces but are able to invade host cells demonstrated in clinical trials and it has detection of the probiotic micro- and survive intracellularly. Such bacteria an excellent safety record. We could organism Escherichia coli Nissle 1917 have made themselves available a privi- demonstrate in vitro antiinvasive activity of (EcN) in vivo. J Microbiol Meth 61: 389- leged niche where they are protected form EcN for Salmonella, Shigella, Yersinia and 398. the host’s immune system and the action Listeria. The antiinvasive effect is EcN- of many antibiotics. Members of this group dose dependent and relies on live EcN. of bacteria are several E. coli pathotypes, The active compound seems to be se- Salmonella, Shigella, Listeria and Myco- creted by EcN. By screening a BAC-library, bacterium tuberculosis. As diverse as the determinant for this activity was cloned these bacteria are their invasion systems. and sequenced. Additionally, the flagellin Elucidation of the molecular fundamentals was identified as the inducing factor for of these interactions (adhesion and human b-defensin 2 expression in Caco-2 invasion) promises to form the basis for cells. Further studies are directed to gain new antiinfective preventions. more insight into properties of EcN related The research group screens selected to its probiotic nature.

Fig. 5: The scanning electronmicroscopical image of non-pathogenic E. coli bacteria

Scientific career: 1975 - 1980 Studies in Biology at the Albert-Ludwigs University in Freiburg i.Br. and Eberhard-Karls University of Tübingen 1986 Dissertation at the Eberhard Karls University of Tübingen Tobias Ölschläger 1986 - 1990 Research fellowship at the Institute of Microbiology II (Prof. V. Braun) 21. März 1952 University of Tübingen 1990 -1992 Research fellowship of the DFG at the Walter Reed Army Institute Dr. rer. nat. Tobias Ölschläger of Research, Washington, DC, SA, (Dr. D.J. Kopecko) Institut für Molekulare Infektionsbiologie 1992-1994 Senior Research Fellow of the National Research Councils of Röntgenring 11 National Academie of Sciences, Washington, DC, USA 97070 Würzburg 1994 Research Group leader at the Institute for Molecular Infection Biology, Telefon: ++49 (0)931 312150 University of Würzburg Fax: ++49 (0)931 312578 1997 Appointment for life as „Akademischer Rat“ [email protected] wuerzburg.de

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3.5.5 Molecular and cellular studies on the pathogenicity of Legionella pneumophila regulatory link of virulence and flagellation. (Michael Steinert, Klaus Heuner) In order to dissect the complex host-pathogen cross talk we have developed Legionella pneumophila is naturally found custom tailored surrogate host systems in fresh water were the bacteria parasitize and tissue models. In this regard the intracellularly within protozoa. Upon aerosol genetically tractable Dictyostelium model formation via man-made water systems, and the lung epithelial barrier system L. pneumophila can enter the human lung proved to be particulary useful. and cause a severe form of pneumonia, called Legionnaires´ disease. Our working Research topics group studies the pathogenicity of Legio- nella as well as the host side of infection. a) By using comparative genomic ap- Moreover we analyze the genome structure proaches we were able to reveal genetic and regulatory networks of this pathogen. differences between virulent and avirulent In these studies we mainly focus on Legionella strains. Moreover, it became specific virulence factors like the peptidyl- evident that L. pneumophila encodes a prolyl cis/trans isomerase Mip (macro- high number of eukaryotic-like proteins phage infectivity potentiator), a cell asso- which reflects the close association of ciated phospholipase (PlaB), a type I se- Klaus Heuner legionellae with host cells. Subsequent cretion system (Lss, Legionella secretion applications of DNA microarrays have 08. Juni 1967 system), a new putative conjugation already provided first insights into the system (type IVA secretion system) and the intracellular gene expression patterns of L. pneumophila. A primary goal of this Academic career: project is to unravel those genes that are 1988-1994 Study of Biology in Würzburg essential for the manifestation of Le- 1994-1997 Dissertation at the Institute for Molecular Infection Biology, gionnaires´ disease. University of Würzburg 1997-2000 Post-Doc at the Institute for Microbiology and Hygiene of the b) In a second project we analyze various Humboldt-University of Berlin (Universital hospital, Charité) pathogenicity factors of L. pneumophila. Since 2000 Research group leader at the Institute for Molecular Infection Here we mainly focus on the cell asso- Biology, University of Würzburg ciated phospholipase (PlaB) and the 2007 Habilitation in Microbiology, Faculty of Biology, Würzburg regulatory link of virulence and bacterial Fellowships and Awards: flagellation. We were able to show that the 1994-1996 Doctoral thesis fellowship „Graduate College: Infektiologie“ (DFG) flagellum is a virulence associated factor 2000-2002 Post doctoral fellowship „European Graduate College: Gene and that the expression of the virulent regulation in and by microbial pathogens“ (DFG) phenotype (transmissive phase) and motility are regulated co- ordinately (Fig. 6). The master regulator of the flagellar regulon is FleQ. Further investigations revealed that FliA and RpoN were also involved in the regulation of genes encoding the filament struc-

Fig. 6: The proposed cascade for regulation of virulence and the flagellum of L. pneumophila. The model correlates with the transition of L. pneu- Dr. rer. nat. Klaus Heuner mophila from the replicative Institut für Molekulare Infektionsbiologie („non-virulent“) to the transmissive („virulent“) phase. Röntgenring 11 Positive (+) and negative (-) 97070 Würzburg regulation is indicated by Tel.: ++49 (0)931-312151 arrows. Dotted lines indicate that the mode of action is not Fax: ++49 (0)931-312578 known yet. S 54, alternative [email protected] sigma-54 factor.

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ture, the basal body and the assembly of found that the Legionella Mip protein binds the flagellum. to collagen which renders this component sensitive for cleavage by a serine protease. c) A third project is dedicated to Legionella This activity finally contributes to the virulence factors which are transported to perforation of the lung epithelial barrier in their targets via secretion systems. We vitro and in vivo (Figure 7). Drug develop- recently identified a first putative type I ments to block this mechanism could be secretion system encoded by the lss locus an entirely new approach to treat Le- (Lss, Legionella secretion system) of L. gionnaires´ disease and might have furt- pneumophila. Using 2 D gel electro- her applications for other pathogens. phoresis and an lssB mutant strain of L. pneumophila Corby we identified a LssB- dependent secreted protein of approxi- Selected references: mately 15 kDa. The identified protein - Brüggemann, H., Hagman, A., Jules, M., exhibits a VirK_Pfam domain. We also Sismeiro, O., Dillies, M.-A., Gouyette, C., Kunst, F., Steinert, M., Heuner, K., Coppee, J.- were able to identify a putative new Y., Buchrieser, C. 2006. Virulence strategies conjugation/ type IV secretion system for infecting phagocytes deduced from the encoded by a genomic island of approxi- transcriptional program of Legionella pneumo- mately 43 kb. The genomic island is phila. Cell. Microbiol. 8: 1228-1240. excised from the chromosom and then able - Steinert, M., Heuner, K. 2005. Dictyostelium Michael Steinert to be transferred to another Legionella as host model for pathogenesis. Cell. Microbiol. 05. Juni 1966 strain by conjugation. 7: 307-314.

d) Wheather or not host organisms become infected by pathogens is the result Academic career: of a complex interplay between host and 1985-1992 study of Biology in Würzburg pathogen genotypes, as well as the 1992-1996 PhD at the University of Würzburg physiological condition of both species. In 1996-1998 Postdoc at the Centers for Disease Control and Prevention, Atlanta, order to also analyze the host side of GA, USA infection we established a genetically 1998- Research group leader at the Institute for Molecular Infection tractable Dictyostelium host model of Biology, University of Würzburg Legionella infection and an in vitro lung 2003 Habilitation at the Faculty of Biology, University Würzburg epithelial barrier system. The analysis of 2006 Offer of W2 professorship in Braunschweig (accepted) the intracellular growth, subcellular locali- Fellowships and Awards: zation and the intracellular activites of 1996-1998 Fellowship of the DFG (German Research Foundation Legionella suggested that Dictyostelium is a representative host-model system. By using mutants of the haploid amoeba Dictyostelium discoideum we were able to Fig. 7: Histopathology of lung tissue sections and distribution of Mip-positive and Mip- identify infection relevant host cell factors negative L. pneumophila strains after intra- and signal transduction pathways. The use tracheal infection of guinea pigs. The infection of a newly developed lung epithelial barrier with the Mip-positive strain results in a confluent bronchopneumonia with an extensive system enabled us to study the tissue neutrophilic infiltration of the alveolar par- invasion of Legionella into the lung. We enchyma.

PD Dr. rer. nat. Michael Steinert Institut für Molekulare Infektionsbiologie Röntgenring 11 97070 Würzburg Tel.: ++49 (0)931-312588 Fax: ++49 (0)931-312578 [email protected]

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3.5.6 Virulence and resistance mechanisms of pathogenic staphylococci coccus epidermidis. The element is highly (Knut Ohlsen, Wilma Ziebuhr) active and causes reversible gene in- activations as well as induction of neigh- Staphylococcus aureus and Staphylo- bouring gene expression. Moreover, mul- coccus epidermidis are the most common tiple IS256 copies can function as cross- causative agents of device-associated over points for homologous recombination nosocomial infections in immunocom- events and contribute therefore to the promised patients and the extraordinary instability of the staphylococcal genome. high resistance rate towards many com- Thus, IS256 seems to represent an monly used antibiotics pose a great important factor for the generation of challenge for the management of these genotypic and phenotypic diversity in these infections. The Staphylococcus research bacteria. The data sugest that the patho- group investigates factors and processes genic potential of a bacterium is not only which are associated with the patho- associated with the presence or abscence genesis of staphylococcal diseases and of virulence factors. In fact, the ability to re- contribute to the establishment of these organize the existing genetic material and bacteria in the hospital environment. to permanently modify its expression is an Staphylococci are very flexible micro- organsisms exhibiting a broad phenotypic and genetic variability. Specifically in S. epidermidis, the ability to form biofilms on smooth artificial surfaces is a typical feature of pathogenic strains whose expression undergoes phenotypic variation. Staphylo- coccus biofilm formation is influenced by external factors and regulatory processes as well as by genetic mechanisms such as phase variation, deletions, mutations and genome rearrangements which are associated with the action of insertion sequences (i.e. IS256). Epidemiological studies revealed that IS256 is a common constituent of the genome of pathogenic Fig. 8: Biofilm formation of Staphylococcus Staphylococcus aureus and Staphylo- epidermidis on a polystyrene surface.

Academic career: 1984-1991 Studies of Medicine; Friedrich-Schiller-Universität Jena 1990-1991 Diploma thesis at the Institute for Clinical Immunology of the University of Jena 1991 State examination Scientific work and positions: 1991-1994 Grant of the „Deutsche Forschungsgemeinschaft“ 1994 Doctoral thesis at the Institute for Molecular Infection Biology, Wilma Ziebuhr University of Würzburg 21. Oktober 1964 1996 Doctorate award of the Medical Faculty of the Würzburg University 1994-1996 Postdoc fellow at the Institute for Medicinical Microbiology of the Friedrich- Schiller-University, Jena PD Dr. med. Wilma Ziebuhr 1996 Group leader at the Institute for Molecular Infection Biology, Institut für Molekulare Infektionsbiologie University of Würzburg Universität Würzburg 2003 Habilitation (lecture qualification) for the subject „Molecular Biology of Röntgenring 11 Infectious Diseases“ D-97070 Würzburg 2006 Offer and Acceptance of the „Reader in Bacteriology“ Postition at the Tel.: ++49 / 931 -312154 University of Belfast Fax. ++49 / 931 - 312578 Senior scientist: [email protected] Dr. Swetlana Kozitskaya

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evolutionary advantage which seems to be Selected references: efficiently utilized by Staphylococci. The - Batzilla, C.F., Rachid, S., Engelmann, S., action of IS elements is an imortant driving Hecker, M., Hacker, J., and Ziebuhr, W. (2006) force in this process enabling the bacteria Impact of the Accessory Gene Regulatory to adapt to changing environmental con- System (Agr) on Extracellular Proteins, codY Expression and Amino Acid Metabolism in ditions and to conquer new ecological Staphylococcus epidermidis. Proteomics niches. 6:3602-3613. A major research topic deals with the - Ziebuhr, W., Hennig, S., Eckart, M., Kränzler, exploration of virulence mechanisms in H., Batzilla, C., Kositzkaya, S. (2006) Noso- staphylococci. Recently, a catheter-related comial infections by Staphylococcus epi- infection model in rats was established. dermidis: how a commensal bacterium turns Using this animal model system patho- into a pathogen. Int J Antimicrob Agents 28:14- genesis of catheter-related infections can 20. be studied in vivo. First, we investigated - Hauck, C.R., and Ohlsen, K. (2006) Sticky the impact of the alternative sigma factor connections: extracellular matrix protein SigB on biofilm formation in vivo and on recognition and integrin-mediated cellular the infectious process. The experiments invasion by Staphylococcus aureus. Curr Opin Microbiol 9:1-7. revealed that sigB deficient bacteria were - Agerer, F., Lux, S., Michel, A., Rohde, M., able to form a biofilm inside the catheter Ohlsen, K., and Hauck, C.R. (2005) Cellular lumen, but they were significantly atten- invasion by Staphylococcus aureus reveals a uated in virulence. Further work using this functional link between focal adhesion kinase model aims at the investigation of the role and cortactin in integrin-mediated internali- of global regulatory molecules such as agr sation. J Cell Sci 118:2189-2200. and arl and general fitness factors for the virulence of the organisms. For this purpose, full genome DNA microarrays of S. aureus and S. epidermidis were developed which are now employed both for gene expression analyses of regulatory mutants and genome comparison studies of pathogenic variants. The approach is completed by investigation of the protein expression patterns using two–dimensio- nal protein gelelectrophoresis. The long term goal of this comprehensive approach is a better understanding of Staphylo- coccus gene regulation which will in turn lead to the identification of novel targets for future antibiotic therapies.

Academic career: 1988-1993 Study of biology at the University of Leipzig Knut Ohlsen 1993-1997 PhD student at the Institute for Molecular Infection Biology, 29. Mai 1966 University of Würzburg, Germany 1997-1998 Postdoctoral fellow at the Institute for Molecular Infection Biology, University of Würzburg 1997 PhD thesis at the Institute for Molecular Infection Biology Dr. rer. nat. Knut Ohlsen 1998- Group leader, at the Institute for Molecular Infection Biology Institut für Molekulare Infektionsbiologie Röntgenring 11 Senior scientist: 97070 Würzburg Dr. Christian Hüttinger Tel.: ++49 (0)931 312155 Fax: ++49 (0)931 312578 [email protected]

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3.5.7 Molecular characterization of pathogenic reactions of Entamoeba histolytica reorganization during phagocytosis. The (Heike Bruhn) extraordinary number of these proteins in such a primitive organism indicates an The protozoon Entamoeba histolytica is essential importance for the survival and the causative agent of human amoe- development of the amoeba. The uni- biasis, the second leading cause of death queness of sequence and architecture of due to parasite infections. 50 Million these proteins without homologues in any people are infected and approximately 100 known genome including the human host 000 of them die annually. Due to the fecal- raises hope of their applicability for oral path of infection, the disease is mostly urgently needed novel antiparasitic drugs. prevalent in developing countries under insufficient hygienic conditions. The amoeba lives as a commensale in the human colon feeding here on bacteria. Occasionally, it will cross the mucosa in an active locomotion and may invade into the tissue thereby - true to its name – exciting severe tissue destruction, which mostly result in serious liver abscesses. The killing of human cells is mainly Heike Bruhn provoked by a family of membrane- 07. April 1965 permeabilising proteins termed amoebapores. The mechanism of their disruptive activity is the formation of stabile oligo- Fig.9: E. histolytica trophozoites filled with phago- mers leading to pores of a defined size, zytosed human erythrozytes. as could be evidenced by a combination of biochemical characterization and structural analysis. The amoebapores are Selected references: the first cytolytic representatives of this - Winkelmann J, Leippe M, Bruhn H (2006): A novel saposin-like protein of Entamoeba protein family, the saposin-like proteins histolytica with membrane-fusogenic activity. (SAPLIPs), and also its first known Mol Biochem Parasitol 147:85-94 . protozoan members. The recently pub- - Bruhn H (2005): A short guided tour through lished genome sequence of E. histolytica functional and structural features of saposin- revealed 16 SAPLIP sequences in addition like proteins. Biochem J 389:249-57 . to the three amoebapores. Beside putative - Leippe M, Bruhn H, Hecht O, Grötzinger J defense molecules with amoebapore-like (2005): Ancient weapons: the three-dimen- activities, some of these proteins are sional structure of amoebapore A. Trends involved in membrane-trafficking and Parasitol 21:5-7

Education and Experience: Since 2001 Research assistant at the Reserach Center for Infectious Diseases, Würzburg 2007 Habilitation in microbiology 1998–2001 Research assistant at the Bernhard Nocht Institute for Tropical Medicine, Hamburg 1995–1998 Postdoctoral fellow at the Gene Center, Ludwig-Maximilians University of Munich Dr. rer. nat. Heike Bruhn 1995 PhD degree of the Heinrich Heine University of Düsseldorf Zentrum für Infektionsforschung 1984 – 1990 Study of Chemistry at the University of Köln Röntgenring 11 Responsibilities and Awards: D- 97070 Würzburg 2006–2007 Fellowship for excellent young investigators of the Federal Germany Government and „Länder“ Tel.: ++49 (0)931 312141 2001–2004 Fellowship of the „higher education and science Fax: ++49 (0)931 312578 programme“ (HWP) of the Federal Government and „Länder“ [email protected] since October 2003 - Project group „Molecular Parasitology“

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3.6 Pathologisches Institut komplexes Zusammenspiel zwischen CXC- Chemokinsignalen, die sowohl von den Die Infektion der Magenschleimhaut mit Tumorzellen selbst als auch von den tumor- Helicobacter pylori (H. pylori) stellt eine der infiltrierenden Immunzellen abstammen. Die- weltweit am häufigsten vorkommenden bak- se Chemokinsignale scheinen vielgestaltige teriellen Infektionskrankheiten des Men- Effekte in der Tumorbiologie (Tumorangio- schen dar. H. pylori kolonisiert den Schleim genese, Wachstumsmuster) zu haben, die über dem Magenepithel und führt zur Ausbil- weit über ihre Funktion als reine chemotakti- dung einer entzündlich-immunologischen sche Moleküle hinausgehen. Wirtsreaktion der Magenmu-kosa, die als Zusätzlich zu der Chemokinexpression selbst chronisch aktive Gastritis bezeichnet wird. werden nach unseren Daten auch die Expres- Am Pathologischen Institut wird in einem DFG sion der Chemokinrezeptoren durch H. pylori geförderten Projekt (EC 203/01) in der moduliert. So wird der CCR7 Rezeptor auf Arbeitsgruppe um Matthias Eck und Bernd dem Magenepithel und auf Magenkarzinomen Schmaußer die entzündlich-immunologische exprimiert und durch H. pylori hochgeregelt. Wirtsreaktion bei der H. pylori Infektion un- Dies ist von besonderem Interesse, da CCR7 tersucht. Diese moduliert zusammen mit eine wichtige Rolle in der Metastasierung von Hans-Konrad Pathogenitätsfaktoren von H. pylori die Karzinomen spielt. Müller-Hermelink Krankheitsausprägung in der Magen- Aber nicht nur auf dem Magenepithel, son- schleimhaut beginnend von der chronisch dern auch auf neutrophilen Granulozyten in 21. Juni 1943 aktiven Gastritis, dem Magen- und Duo- der chronisch aktiven Gastritis führt H. pylori denalulcus bis hin zum Magenkarzinom und zu einer Regelung von Chemokinrezeptoren. MALT-Lymphom. Eine wesentliche Rolle spie- Dabei konnte die Arbeitsgruppe zeigen, dass len hierbei das Chemokin/ Chemokin- H. pylori den CXCR1- und CXCR2-Rezeptor rezeptorsystem als auch Rezeptoren der auf neutrophilen Granulozyten herunter- „innate immunity“, z.B. Toll-like Rezeptoren.. reguliert. Diese Rezeptorherunterregulierung In der H. pylori Gastritis konnte die Arbeits- erfolgt über einen IL-8, TNF-α und H. pylori gruppe zeigen, dass CXC-Chemokine das LPS unabhängigen neuen Mechanismus und Entzündungsinfiltrat in der Magenschleim- ist auf mRNA Ebene abhängig von der Cag- haut modulieren. Die Chemokine IL-8 und Pathogenitätsinsel. Die Herunterregulierung Groa, werden durch H. pylori in den Epithel- des CXCR1- und CXCR2-Rezeptors auf zellen induziert werden und spielen eine neutrophilen Granulozyten durch H. pylori wichtige Rolle bei der Wanderung der neu- scheint einen neuen Pathomechanismus Prof. Dr. med. H. K.Müller-Hermelink trophilen Granulozyten von den Schleim- während der H. pylori Infektion darzustellen, Vorstand des Pathologischen Institutes hautgefäßen in das Magenepithel., während der Migration und Aktivierung von neutrophilen der Universität Würzburg IP-10 und MIG, die in Makrophagen exprimiert Granulozyten in der Magenmukosa beeinflußt. 97080 Würzburg, werden, über den korrespondierenden Weiterhin werden die Toll-like Receptoren Josef-Schneider-Str. 2 Chemokinrezeptor CXCR3 zur Rekrutierung (TLRs) in den H. pylori assoziierten Erkran- Tel. ++49 (0) 931 201-47776 der inflammatorischen T-Zellen in die Mucosa kungen untersucht. TLRs können im Gegen- Fax: ++49 (0) 931 201-47440 beitragen. satz zu den Chemokinrezeptoren direkt bak- [email protected] Im Magenkarzinom besteht ebenfalls ein terielle Liganden erkennen und so das

Scientific career: Society Membership: 1962- 1968 Studies of Medicine at the Universities of Tübingen, Montpellier and Kiel Bavarian Society of Gastroenterology. 1968 Internship (Medizinalassistent), Institute of Pathology of the University of Kiel European Association of Hematopathology. 1969 Internship, Universitäts-Frauenklinik Kiel, Medizinische Universitäts-Klinik European Society of Pathology. Kiel und Chirurgische Universitätsklinik im Krankenhaus Westend, Berlin. German Cancer Society. 1970 M.D. German Society of Pathology. 1976 Habilitation in Pathology German-Austrian Society of Hematology and Faculty and Hospital Positions: Oncology. 1970- 1985 Affiliated at the Institute of Pathology, University of Kiel International Academy of Pathology, British Di- 1985 Professor of Pathology and Head of Department, University of Würzburg. vision 1991 - 1994 Dean of the Medical Faculty, University of Würzburg. International Academy of Pathology, German 1991 - 1998 Speaker of SFB 172 „Molecular Mechanisms of Cancerogenesis“ Division 1996 Speaker of the Interdisciplinary Center of Clinical Research, Würzburg (IZKF) Society of Hematopathology 1998 - Speaker (together with Prof. E. Serfling) of DFG Research Group: „Altered Transcription in Lymphoid Tumours“. 2000 Speaker of the GraduateCollege 639 of the DFG „Mechanisms of Tumor Instability“

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Chemokin/ Chemokinrezeptorsystem und die cruitment of inflammatory T-cells into the nachfolgende immunologische Antwort beein- mucosa. flussen. In gastric carcinoma also a complex interplay Es konnte gezeigt werden, dass sowohl das between CXC chemokines exists, which derive Magenepithel in der H. pylori Gastritis als auch as well from tumor cells as from tumorinfiltrating Magenkarzinomzellen selbst TLRs exprimieren immune cells. These chemokine signals have und somit mit H. pylori interagieren können. Die pleiotropic effects in tumorbiology (tumor TLR Expression im Magenepithel ist polarisiert angiogenesis, growth pattern) far beyond in apikales oder basolaterales epithelialen Zell- chemotaxis. kompartiment und wird dynamisch durch According to our data not only chemokines, but H. pylori beeinflusst. Dies weist auf eine zentra- also chemokine receptors are regulated by le Rolle der TLRs in der mukosalen Immun- H. pylori. The CCR7 receptor is expressed on antwort gegen H. pylori hin. gastric epithelium and on gastric carcinoma cells Um eine direkte Rolle von H. pylori in der Entste- and is upregulated by H.pylori. This may be hung des Magenkarzinoms näher zu charakteri- important as CCR7 plays a crucial role in the sieren, gehen wir in einem weiteren DFG geför- metastasis of carcinoma. derten Projekt interdisziplinär in Zusammenar- However, H. pylori regulates chemokine re- beit mit dem Institut für Toxikologie der Frage ceptors expression not only on gastric epithelium, einer direkten Gentoxizität von H. pylori nach. but also on neutrophils in chronic active gastritis. Mittels in vitro micronucleus assay fanden sich The group could demonstrate that H. pylori Hinweise auf einen durch H. pylori induzierten downregulates the CXCR1 and CXCR2 receptor DNA Schaden. In laufenden Untersuchungen soll on neutrophils. This down-regulation results by geklärt werden, ob H. pylori Virulenzfaktoren wie a new mechanism independend of IL-8, TNF-a z.B. CagA oder H. pylori Stämme aus verschie- and H. pylori LPS and is on mRNA level denen geographischen Regionen mit unter- dependend on the cag pathogenicity island. schiedlicher Karzinomhäufigkeit diese Mikro- Downregulation of the CXCR1 and CXCR2 kernbildung beeinflussen. receptor on neutrophils may present a new pathomechanism in H. pylori infection, which 3.6 Institute of Pathology influences migration and activation of neutrohils in the gastric mucosa. Infection of the gastric mucosa with H. pylori is In further studies Toll-like receptors (TLRs) in one of the most common infections worldwide H. pylori associated diseases were investigated. in human beings. H. pylori colonizes the In contrast to chemokine receptors TLRs mucous overlying the gastric epithelium recognice bacterial ligands and influence the leading to an inflammatory host response in chemokine/chemokine receptor system and the the gastric mucosa called chronic active resulting immune response by this way. gastritis. It has been shown that as well gastric epithelium At the Institute for Pathology the mucosal im- in H. pylori gastritis as tumor cells of gastric mune response in H. pylori infection is studied carcinoma themseves are able to express TLRs, by the group of Matthias Eck and Bernd which enables them to interact with H. pylori. Schmaußer. The interplay between H. pylori and TLR expression of gastric epithelium is highly the host modulates the development of polarized in apical and basolateral cell comp- disease in the gastric mucosa starting from artments. This polarization is dynamically chronic active gastritis and gastric or duodenal influenced by H. pylori indicating a central role of ulceration until the gastric carcinoma and MALT- TLRs in the mucosal immune response directed type lymphoma. In this context the chemokine/ against H. pylori. chemokine-receptor system and receptors of To invesigate a direct role of H. pylori in gastric the innate immunity e.g. Toll-like receptors play carcinogenesis, we evaluate in another DFG an important role. sponsored research project in cooperation with In H. pylori gastritis the group has demon- the Institute for Toxicology the genotoxicity of H. strated that CXC-chemokines modulate the pylori. By in vitro micronucleus assay we were inflammatory infiltrate in the gastric mucosa. able to detect DNA damage induced by H. pylori. The chemokines IL-8 and Groa, which are In current studies the group is going on to clarify induced by H. pylori, seem to play the central whether H. pylori virulence factors as CagA or H. role in the migration of neutrophils from pylori strains from different geographical regions mucosal vessels into the gastric epithelium, with varying carcinoma incidence influence this whereas IP-10 and MIG contribute via the micronucleus formation. corresponding receptor CXCR3 to the re-

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3.7 Medizinische Klinik und Poliklinik I

Professor Dr. Georg Ertl Medizinische Universitätsklinik Würzburg Josef-Schneider-Str. 2 97080 Würzburg Tel.: ++49 -(0)9 31-2013 63 00 Georg Ertl Fax: ++49 -(0)9 31-20136302 12. Juni1950 in Neuburg/ Rhein [email protected]

1956 - 1968 Primary school in Neuburg, Highschool in Karlsruhe 1968 – 1974 Medical student in Mainz and Graz 1974 – 1975 Internal medicine in Pfronten (surgery) and the University Hospital of Mainz (internal medicine) 1975 Medical Doctor (M.D.) at the University of Mainz 1975 – 1976 Military Service as Medical Officer (compulsory) 1977 – 1979 Research fellow at the Physiological Institute, University of Düsseldorf (Professor Dr. Dr. W. Lochner) 1979 – 1980 Research fellow (Deutsche Forschungsgemeinschaft) at the Harvard University and Peter Bent Brigham Hospital, Boston, USA (Professor Dr. Braunwald) 1981 Resident for internal medicine at the Medical University Hospital of Würzburg (head: Professor Dr. K. Kochsiek) 1986 „Privatdozent“ (assistant professor) at the medical faculty of Würzburg, internist, assistant medical director and head of the intensive-care unit for internal medicine 1987 Cardiologist 1991 – 1994 Associate professor (C3) and vice director of the Department of Internal Medicine, University Hospital Würzburg 1995 – 1998 Chairman of Cardiology at the Faculty of Clinical Medicine Mannheim of the University of Heidelberg and Director of the Department of Internal Medicine at the Hospital of Mannheim, medical vice director of the Hospital of Mannheim Since 1999 Chair of Internal Medicine and Director of the Department of Internal Medicine, University of Würzburg 2004-2006 Dean of the Medical Faculty of the University of Würzburg

Commissions: Dean of the medical faculty of the University of Würzburg 2004 - 2006 Member of the managing board of the Medizinische Universitätsklinik 2004 - 2006 Member of the board of the Deutsche Gesellschaft für Kardiologie (German Association of Cardiology) Speaker of the Sonderforschungsbereich SFB 355 „Pathophysiologie der Herzinsuffizienz“ (Pathophysiology of Heart Failure) – 2004; Vice- Speaker of the Sonderforschungsbereich SFB 688 „Kardiovaskuläre Zell-Zellinteraktionen“ and of the BMBF Kompetenznetz „Herzinsuffizienz“ Memberships: Deutsche Akademie der Naturforscher, Leopoldina, American Federation for Medical Research American Association for the Advancement of Science, American Society of Physiology Council of Basic Science of American Heart Association Deutsch-Chinesische Gesellschaft für Medizin e.V., Deutsche Gesellschaft für Innere Medizin (Vorsitzender 2007/2008), Deutsche Gesellschaft für Herz- und Kreislaufforschung (Vorstandsmitglied) Deutsche Gesellschaft für internistische Intensivmedizin, Vorstandsmitglied der Deutschen Herzstiftung e.V. – 2004. Deutsche Physiologische Gesellschaft, Europäische Gesellschaft für Kardiologie („Fellow“) European Society for Magnetic Resonance in Medicine and Biology (ESMRMB), Gesellschaft für Fortschritte in der Inneren Medizin Grants and Awards: - Kompetenznetz Herzinsuffizienz BMBF (Network of Competence „Heart Failure“) - Interdisziplinäres Netzwerk Herzinsuffizienz BMBF (Interdisciplinary Network „Heart Failure“) - Sonderforschungsbereich SFB 688 „Kardiovaskuläre Zell-Zellinteraktionen“

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3.7.1 Untersuchungen zum Einfluss der wurden mittels Durchflusszytometrie und mikrobiologischen Mundflora auf die konfokaler Mikroskopie charakterisiert. Inzidenz eines akuten Myokardinfarktes (MUNDART – Studie): Eine funktionelle Charakterisierung erfolgte in Gegenwart spezifischer αv - Untersuchungen der letzten Jahre konnten Inhibitoren bezüglich ihres migratorischen eine Verbindung zwischen Atherosklerose, und invasiven Verhaltens. Neben der koronarer Herzkrankheit, Herzinfarkt und Proteinexpression und Phosphorylierung Parodontitis aufzeigen. Patienten, die an wurde auch Apoptose untersucht. Hapt- einer Parodontitis leiden, zeigen ein 1,5- otaktische Stimulation durch Vitronektin fach erhöhtes Risiko für koronare Herz- führte zu einer dosisabhängigen Zu- erkrankungen (KHK), 2,2-fach für letale nahme der Zellmigration und konsekutiv KHK und 2,8-fach für Schlaganfall, re- zu einer Zunahme der Phosphorylierung spektive. Die biologischen Grundlagen von Tyrosin durch die focal adhesion sind zur Zeit aber noch unklar. Ziel der kinase (FAK). Dies konnte durch einen αv vorliegenden Studie ist es, Patienten nach -Inhibitor vollständig unterdrückt werden. akutem Myokardinfarkt serologisch und Zusätzlich unterbindet der αv -Inhibitor die mikrobiologisch auf das Vorhandensein chemotaktische Migration. Die gesteigerte von Zeichen einer akut abgelaufenen Ent- Tyrosinkinasephosphorylierung im Be- zündung mit den wichtigsten parodon- reich der glatten Muskelzellen konnte topathogenen Bakterien Actinobacillus mittels konfokaler Mikroskopie bestätigt actinomycetem-comitans (Aa), Porphy- werden. Die in vitro – Invasion der hCA- romonas gingivalis (Pg), Treponema SMC war in Gegenwart eines ±v Inhibitors denticola (Td), Bacteroides forsythus (Bf), ebenfalls deutlich reduziert und ging mit Eikenella corrodens (Ec) und Spirochäten einer reduzierten Expression der Matrix – zu untersuchen. Der mikrobiologische Metalloproteinase 2 (MMP-2) einher. Dies Status dieser Patienten wird mit dem einer zeigt, dass eine ±v Inhibiton die Tyrosin – Probandengruppe gleicher Alters- und Kinase Phosphorylierung an den An- Geschlechtsverteilung verglichen, die bei heftungsstellen beeinflusst, vor allem einer Herzkatheteruntersuchung keine durch die FAK, und zusätzlich die Se- Anzeichen einer koronaren Herzkrankheit kretion von MMP-2 verringert, was zu einer aufweist. In dieser randomisierten pro- verlangsamten Migration und Invasion der spektiven Studie sollen 160 Patienten an hCASMC führt. den Universitätsklinika Würzburg und Münster eingeschlossen werden, ge- genwärtig sind bereits 89 Patienten in der Studie eingeschlossen. 3.7 Clinic for Internal Medicine I 3.7.2 Kontrollierte Migration der glatten Muskelzellen mittels Beeinflussung der 3.7.1 Analysis of the impact of oral micro- Matrixproteine und Rezeptoren der Inte- biological environment on the incidence grin – Familie: of myocardial infarction (MUNDART – trial):

Kooperation der Medizinischen Klinik mit dem Zentrum für Infektionsforschung Recent investigations could demonstrate Eine überschiessende Migration der a correlation between atherosclerosis, glatten Muskelzellen ist ein Schlüs- coronary heart disease, myocardial selproblem bei der koronaren Restenose infarction and parodontitis. Patients nach Dilatation. Obwohl extrazelluläre suffering from paradontitis have a 1.5 fold Matrixproteine und Rezeptoren der Integrin higher risk for coronary heart disease, 2.2 – Familie eine bedeutende Rolle im fold higher risk for fatal myocardial Prozess der Restenose darstellen, ist die infarction and 2.8 fold higher risk under- Regulation der Migration der glatten lying a stroke. The underlying biological Muskelzellen molekular noch nicht auf- mechanisms are unclear. It is the aim of geklärt. Primäre humane glatte Muskel- the present study to investigate the impact zellen aus Koronararterien (hCASMC) of the most parodontopathogen bacteria

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(Actinobacillus actinomycetemcomitans inhibitor abolished PDGF-BB-stimulated (Aa), Porphyromonas gingivalis (Pg), chemotactic migration. CM confirmed the Treponema denticola (Td), Bacteroides increased tyrosine phosphorylation at VN- forsythus (Bf), Eikenella corrodens (Ec) initiated focal contact sites in SMC, that and Spirochetes in patients suffering from was reduced upon αv-inhibition. In vitro an acute myocardial infarction. Serological invasion of hCASMC was severely com- and microbilological analysis will be promised in the presence of the integrin performed in patients with myocardial αv -inhibitor paralleled by decreased infarction as well as in patients where a levels of secreted matrix metalloprotease coronary heart disease could be ruled out 2 (MMP-2). Therefore Integrin αv-inhibition by a coronary angiogramm. In this pro- abrogates tyrosine phosphorylation at spective, randomized, two center trial 160 focal adhesion sites, affecting in particular patients from the university hospitals of FAK, and diminishes MMP-2 secretion Würzburg and Münster will be included, leading to reduced migration and invasion currently 89 patients are enrolled. of hCASMCs.

3.7.2 Controlling migration of smooth muscle cells by modulation of matrix proteins and receptors of the integrin family:

Cooperation of the Medical Clinic and Center for Infectious Diseases Aberrant migration of smooth muscle cells (SMC) is a key feature of restenosis. Though extracellular matrix proteins and their receptors of the integrin family play a critical role in this process, their contribution to cell migration in response to different stimuli and their role in regulating phenotypic changes required for invasive motility of SMC is ill defined on the molecular level. Primary human Selected references: coronary artery smooth muscle cells (hCASMC) were characterized by flow - Nahrendorf M, Hu K, Frantz S, Jaffer cytometry and confocal microscopy (CM). FA, Tung CH, Hiller KH, Voll S, Nord- They were functionally analysed in the beck P, Sosnovik D, Gattenlohner S, presence of a specific integrin ±v inhibitor Novikov M, Dickneite G, Reed GL, upon replating onto extracellular matrix Jakob P, Rosenzweig A, Bauer WR, Weissleder R, Ertl G (2006) Factor XIII substrates and upon growth factor stimu- deficiency causes cardiac rupture, lation with regard to their migratory and impairs wound healing, and aggravates invasive potential. Protein expression and cardiac remodeling in mice with phosphorylation were investigated by myocardial infarction. Circulation. Western Blot (WB) analysis and zymo- 113(9):1196-202. graphy, apoptosis was dentified by an- - Kuhlencordt P, Hötten S, Schödel J, nexin-V staining. In hCASMC plated on Rützel S, Hu K, Widder J, Marx A, vitronectin (VN), αv-containing integrins Huang PL, Ertl G (2006) Athero- were localized at focal adhesion sites. protective effects of neuronal nitric Haptotactic stimulation through VN led to oxide synthase in apolipoprotein e a dose-dependent increase in cell mi- knockout mice. Arterioscler Thromb gration and concomitantly to enhanced VascBiol.26 (7):1539-44. - Bauersachs J, Thum T, Frantz S, Ertl tyrosine phosphorylation of focal ad- G (2005) Cardiac regeneration by hesion kinase (FAK). Both events were progenitor cells—bedside before completely blocked by an integrin αv- bench? Eur J Clin Invest. 35(7):417-20 inhibitor. Additionally, the integrin αv-

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3.8 Medizinische Klinik und innovative stem cell transplantation pro- Poliklinik II - Clinic for Internal gramme also creates severe forms of Medicine II immunosuppression and thus a lot of infectious complications. Therefore together Includes the following disciplines of with the section for Infectious diseases Internal Medicines: (Head: Prof. Klinker) which concentrates - Gastroenterology/Hepatology on HIV infection and different forms of - -Hematology and Oncology opportunities infections we have a large - Rheumatology and Immunology patient population suffering from oppor- - Psychosomatic medicine tunistic infections. Thus several research - Infectious diseases projects have been initiated to look at diffe- A newly created centre of stem cell rent forms of opportunistic infections (fungal Hermann Einsele transplantation has started its trans- infections, CMV infections, EBV and respi- 10.01.1958 plantation programme in March 2005. ratory virus infections, toxoplas-mosis). Already in 2006 the stem cell trans- This research is funded by two large grants Professor Dr. med. Hermann Einsele plantation programme (50 allogeneic/150 from the EU (EU FP 6 Allostem, EU FP6 Medizinische Klinik und Poliklinik II allogeneic stem cell transplantations) has Strep MANASP), the Deutsche Forschungs- Klinikstraße 6-8 become one of the three largest in gemeinschaft (DFG SPP 1160: Analysis of 97070 Würzburg Germany. Innovative techniques in stem the interaction between Aspergillus fumi- Tel.: ++49 (0)9 31- 2 01 - 70000 cell transplantation (cord blood trans- gatus and human immune effector cells Fax: ++49 (0)9 31- 2 01 - 70730 plantation, haploidentical stem cell trans- and the induction of innate and adaptive [email protected] plantation) are performed. The large and immune responses to this pathogen),

1977 – 1984 Eberhard-Karls-Universität Tübingen Lord Owens University Manchester Guy´s Hospital (Imperial College) Lon- don 1984 – 87 Research Fellow, Department of Haematology/Oncology/ Rheumatology/Immunology, University of Tübingen 1986 MD Thesis: Membrane alterations of red bloods cells in liver disease (summa cum laude) 1988 Fellow Max-Planck-Institute for Biochemistry, Martinsried 1989 - 1996 Member of the Research Network SFB 120 (Immunogenetics and Allo-SCT) 1991 Board Certificate: Internal Medicine 1992 Assistant Professor 1993 Oberarzt since 1993 Member of ASH, EBMT, EBMT working parties Infectious Disease and Chronic Leukemia since 1995 Head of the Allogeneic Stem Cell Transplantation Programme 1996 Board Certificate: Hematology/Oncology since 1997 Member of the SFB 510 (Stem cell transplantation and Antigen Processing) since 1999 Associate Professor since 1999 Chairman of the German Study Group Multiple Myeloma (DSMM) 12/1999 Visiting Professor FHCRC, Seattle 12/2000 Visiting Professor City of Hope Hospital, Duarte 6/2000 Member of the Board of the German Society of Stem Cell Transplantation (DAG-KBT) 7/2003 van Bekkum- Award European Society of Blood and Marrow Transplantation 4/2004 Chairman of the Infectious Disease Working Party of the EBMT Board of the European Blood and Marrow Trans plantation Society Member of the German Lymphoma NetWork 12/2004 Director of Medizinische Poliklinik Julius-Maximilians-University, Würzburg Research Activities: Immune reconstitution after Stem Cell Transplantation/GvHD (SFB 120 1988-1996), Local virus infections and associated Cytokine Dysregulation in Autoimmune Diseases (BMBF 1988-1994), Herpes Virus Infections in Transplantation (BMBF 1993- 2000), Molecular Diagnostics for Fungal Infection (Fortüne-Programme, Krebshilfe, since 1998 ), Adoptive T cell therapy after Stem Cell Transplantation (SFB 510, since 1997), National Genome Network (TübinGenom) 2001- 2004, Genetic epidemiology of invasive Aspergillosis, EU, FP6 Integreated Project: Allostem:Immunotherapy for CMV/EBV infection (start 02/2004), EU FP6 NoE Euronet-Leukemia „Supportive Care“ , Jose-Carreras-Foundation: Genetically modified T cells to combat Myeloma cells, EU FP6 MANASP „Development of Novel Management strategies for invasive aspergillosis“, DFG: SPP 1160 since 2004 „Analysis of the interaction between ASpergillus fumigatus and human immune effector cells and the induction of innate and adaptive immune responses to this pathogen“ , DFG: SFB 479 „Regulation der Herpesvirus-spezifischen T-Zell Immunität“, EU FP 6 MANASP "Development of Novel Management strategies for invasive aspergillosis (start 01/2007).

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Deutsche Krebshilfe and also by several fektion und der chronischen Virushepatitis industrial partners. In addition a new project B und C durchgeführt. Darüber hinaus er- in the SFB 479 (Regulation der Herpes- folgen in enger Kooperation mit dem virus-spezifischen T-Zell Immunität) has Schwerpunkt Hämatologie diverse Studi- been initiated looking at specific aspects en zur systemischen antimykotischen The- of HCMV infections. Further details of these rapie bei hämatologisch/onkologischen scientific projects are outlined below. Patienten (Dr. W. Heinz). Clinical studies investigate the role of adoptive T cell therapy and DC vaccination Der Schwerpunkt Infektiologie ist klini- for CMV, EBV and adenovirus infection and sches Zentrum in den vom Bundes- invasive fungal infection. ministerium für Bildung und Forschung Research Group has an international (BMBF) geförderten Kompetenznetzwerken reputation for performing immunothera- „HIV/AIDS“ und „Hepatitis“. Im Jahre 2005 peutic studies for opportunistic infections. hat sich das Studienzentrum für das welt- weite Studiennetzwerk für strategische HIV- Studien „INSIGHT“ (International Network for Strategic Initiatives in Global HIV Trials) Schwerpunkt Infektiologie des National Institutes of Health/USA ( http:/ (Prof. Dr. H. Klinker) /www.insight-trials.org ) qualifiziert.

Der Schwerpunkt „Klinische Infektiologie“ Im Leber-/Infektionslabor werden Spezial- (Leiter: Prof. Dr. Klinker) der Medizinischen untersuchungen zur quantitativen Leber- Klinik und Poliklinik II der Universität befin- funktionsdiagnostik und zum Therapeuti- det sich in Gebäude C6 und Gebäude D20 schen Drug Monitoring von Virustatika und (wissenschaftliches Labor) am Standort Antimykotika durchgeführt. Insgesamt er- .Luitpoldkrankenhaus. folgten im Zeitraum 2005/2006 über 40.000 Die Station „Schottmüller“ (20 Betten) ist Messungen. die Infektionsstation für Erwachsene des Der Schwerpunkt der Arbeiten liegt in Un- Universitätsklinikums. Es werden dort Pa- tersuchungen zur Pharmakokinetik von tienten mit einem breiten Spektrum infekti- HIV-Protease-Inhibitoren (PI) und Nicht ös bedingter Erkrankungen behandelt. Nukleosidischen Reverse Transkriptase- Schwerpunkte in Diagnostik und Therapie Inhibitoren (NNRTI) im Rahmen der Hoch- stellen die AIDS-Erkrankung, akute und aktiven Antiretroviralen Therapie (HAART) chronische Virushepatitiden, Organ- bei Patienten mit HIV-Infektion, daneben tuberkulosen, Infektionen mit multresisten- wurde eine Plasmakonzentrationbe- ten Erregern, infektiöse Darerkrankungen stimmung von Azol-Antimykotika neu eta- und opportunistische Infektionen unter bliert. Immunsuppression bei Orgatransplan- tierten oder unter Chemotherapie dar. Im Jahre 2005 wurde der Schwerpunkt Im Zeitraum 2005/2006 wurden ca. 1.700 Infektiologie von der Deutschen Gesell- Patienten stationär behandelt. Bereits seit schaft für Infektiologie (DGI) als „Zentrum 2002 wird klinikweit und für die Region ein Infektiologie (DGI)“ zertifiziert. Der Schwer- Konsiliardienst „Klinische Infektiologie“ punktleiter hat neben der Bezeichnung angeboten. „Infektiologe (DGI)“ (2003) im Jahre 2005 Die Infektionsambulanz in Bau C6 ver- die im Rahmen der aktualisierten Weiter- zeichnete im Zeitraum 2005/2006 rund bildungsordnung der Bayerischen Landes- 7.000 Patientenbesuche, 600 Patienten ärztekammer neu geschaffene Zusatz- wurden erstmals zugewiesen. Das Krank- weiterbildung „Infektiologie“ erworben und heitsspektrum umfasste vor allem die HIV- erhielt im selben Jahr die volle Weiter- Infektion und chronische Virushepatitiden. bildungsbefugnis für diesen Bereich. Da- Die Spezialambulanz zeichnet sich als mit war der Schwerpunkt Infektiologie die überregionales Zentrum durch eine hohe erste Einrichtung in Deutschland, in der die Studienaktivität aus. So werden zahlreiche, gesamte Bandbreite der Qualifikationen im nationale und internationale klinische Stu- Bereich der klinischen Infektiologie vorge- dien insbesondere im Bereich der HIV-In- halten werden.

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Division of Infectious Diseases respectively. In addition and in close (Prof. Dr. H. Klinker) cooperation with the Department of Haem- atology, trials concerning invasive fungal The division of Infectious Diseases (head: infections in haematologic or oncologic Prof. Dr. Klinker) of the Medizinische Klinik patients are performed (Dr. W. Heinz). und Poliklinik II, is located in building C6 and building D20 (scientific laboratory) of The section of Infectious Diseases is a the Luitpoldkrankenhaus. clinical center of the „German Competence Our ward, named by H. Schottmüller, is Network on HIV/AIDS“ and the „German caring for up to 20 patients and is equipped Competence Network on Hepatitis“, for infectious diseases in adult patients. A sponsored by the Bundesministerium für broad range of different infections is treated Bildung und Forschung (BMBF). In the year there. Main focus in diagnostics and 2005, the study-center qualified for the therapy are HIV and AIDS, acute as well as worldwide study-network for strategical chronic viral hepatitis, tuberculosis and HIV-studies „INSIGHT“ (International infections with multiresistant bacterias. Network for Strategic Initiatives in Global Besides that, infectious diarrhea and HIV Trials) sponsored by the National Ins- opportunistic infections in immuncom- titutes of Health/USA (http://www.insight- promised hosts, i.e. after chemotherapy or trials.org). organ transplantation are commonly seen. In 2005/2006 a total of about 1.700 Our laboratory is specialized in the de- inpatients were treated on our ward. Already velopment and implementation of methods in 2002 we started providing a consulting for an evaluation of quantitative liver function service on clinical infectiology for the and therapeutic drug monitoring of viro- university, and the clinicians and hospitals static agents and antibiotics. In 2005/2006 in the region. over 40.000 analyses in this field could be Our outpatient care unit had nearly 7.000 performed. patient contacts in 2005/2006, 600 thereof Main focus is the pharmacokinetic eva- were seen for the first time. Regarding luation of HIV protease inhibitors (PI) and these outpatients the clinical spectrum was non nucleoside reverse transcriptase primarily focussed on HIV infection and inhibitors (NNRTI) during highly active chronic viral hepatitis. antiretroviral therapy (HAART) in patients The outpatient clinic of infectious diseases with HIV-infection. is known cross-community as a center performing many clincal trials. Various na- In 2005 the division of infectious diseases tional or international clincal trials are was certified as „Zentrum Infektiologie performed especially concerning infection (DGI)“ (center of infectious diseases) from with HIV and chronic hepatitis B or C, the German Association of Infectiology (DGI). After having already acquired the certificate of specialisation in infectiology („Infektiologe DGI“) in 2003, the head of the center also acquired the title of further professional training in infectiology con-ferred from the Bavarian Medical Asso-ciation as well as the license of further professional education in the field of infectiology in 2005. This center of infec-tious diseases was the first one in Germany offering all qualifications ac-quirable in clinical infectiology.

High pressure liquid chromatographic (HPLC) methods for determination of Fig.1: HPLC illustration of ribavirin plasma concentration (+= Ribavirin 3.000 ng/ plasma levels of HIV-1 Protease-Inhibitors ml, Δ = Internal Standard (3-Methylcytidin-Methosulfat) saquinavir, indinavir, ritonavir, nelfinavir,

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amprenavir, lopinavir, atazanavir, and the non-nucleoside reverse transcriptase- tipranavir were developed in our laboratory inhibitor efavirenz. Concentrations of and evaluated for routine clinical use. nevirapine, another NNRTI, were moni- Current research aims at the long-term tored by a gas chromatographic setup with efficacy especially of protease inhibitor NP-detection during antiretroviral therapy containing regimens. The main focus of in patients with HIV infection. this research is the improvement of protease inhibitor bioavailability by co- Another topic of research was focussed on administration of small doses of ritonavir. the determination of nucleoside reverse As a potent inhibitor of the major cytochrome transcriptase inhibitors (NRTI) and inves- P450 drug-metabolizing enzyme CYP3A, tigations concerning the role of nucleoside ritonavir substantially increases the bio- analogues in mitochondrial toxicity during availability of other, co-administered HAART . protease inhibitors. Thus, combination NRTIs inhibit the synthesis of mitochondrial protease inhibitor-therapy results in DNA, are associated with cytotoxicity based increased plasma levels and in an in- respiratory chain function disorders and creased half-life of the boosted PI. This thus possibly also affect the de novo allows to reduce the dose and dosing synthesis of uridine. The intravenous or oral Hartwig Klinker frequency of PIs. Especially to reduce the supplementation of uridine has been 27.08.1955 in Bielefeld dosing frequency often results in a better suggested to be of potential benefit in Prof. Dr. med. Hartwig Klinker patient‘s compliance. improving the therapeutic index of some Leiter des Schwerpunktes Infektiologie It could be demonstrated that therapeutic cancer medication and also in abrogating Medizinische Klinik und Poliklinik II drug monitoring (TDM) of PI plasma the mitochondrial toxicity of anti-HIV Klinikum der Universität Würzburg concentrations may prove useful in opti- nucleoside analogues. Josef Schneider-Str. 2 mizing antiretroviral therapy. Multivariate It has been demonstrated in vitro and in 97080 Würzburg analysis showed PI plasma concentrations animal models that uridine may abrogate Tel 0931/201-36020 to be an independent predictor of HIV-RNA such mitochondrial toxicity and possibly Fax 0931/201-36022 evolution. even in humans. Uridine therefore is likely [email protected] Another HPLC method was developed for a candidate for further clinical studies in www.medpoli.uni-wuerzburg.de/hepinf

1976 – 1982 studies in medicine at the University of Würzburg 1984 M. D., Julius-Maximilians-Universität Würzburg Career history: 1982 – 1995 resident for internal medicine, Medizinische Universitätsklinik Würzburg, (head: Prof. Dr. K. Kochsiek) 1995 – 2000 senior physician, „Schwerpunkt“ of hepatology and infectious diseases, Medizinische Universitätsklinik, since 1998 Medizinische Poliklinik der Universität Würzburg (head: Prof. Dr. K. Wilms, since 2005: Prof. Dr. H. Einsele) 2000 – Head of the „Schwerpunkt“ of hepatology and infectious diseases, Medizinische Poliklinik der Universität Würzburg Licensure/Certifications: 1982 Medical Licensure (Approbation als Arzt) 1989 Certificate for Internal medicine 1990 Certificate for gastroenterology 2002 Certificate for the field of infectious diseases (DGI) 2005 Certificate infectious diseases (BLÄK) Academic Appointments: 1998 Habilitation for Internal medicine/Privatdozent (assistant professor), Julius-Maximilians-Universität Würzburg 2004 Apl. Professor, Julius-Maximilians-Universität Würzburg Major Assignments: since 1991 member of the Hygienekommisssion, Klinikum der Universität Würzburg since 1992 member of the Arzneimittelkommission, Klinikum der Universität Würzburg 2001-2005 member of the Klinikumskonferenz, Klinikum der Universität Würzburg Since 2005 member of the „Lenkungskreis HIV/AIDS in Western Cape/South Africa“ of the Bavarian Staatskanzlei 2006 member of the German hepatitis B therapy consensus group 2007 member of the scientific Board of the „3. Deutsch-Österreichischer AIDS-Kongress“ 2007 member of the German HIV/AIDS therapy consensus group

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HIV-patients, aimed at alleviating the haematological malignancies, especially mitochondrial toxicities of NRTIs. in those with acute myeloic leukemia or For these studies, it is important to have who are undergoing allogenic stem cell access to an analytical method which is transplantation. These patients often able to determine the uridine concen- receive a number of different drugs for the trations in HIV-patients without interfering underlying disease, prophylaxis or treat- with the nucleosides in antiretroviral drug ment of complications like graft versus host combinations. In order to evaluate uridine disease. Therefore, drug interactions are levels in humans a very sensitive and a relevant problem in daily medical care. specific high performance liquid chromatographic method for the determination of Voriconazole and posaconazole are broad- uridine in serum was developed. ly used in treatment and in secondary prophylaxis of IFI. Like all azole anti- The standard of care in chronic hepatitis C mycotics, they are metabolized by CYP improved markedly and response rates P450-system and show inhibiting and as have multiplied in recent years. Treatment well inducing activity for several isoenzymes options to achieve higher sustained of CYP (2C9, 2C19 and 3A4). Only a few is virological response rates not only in the known about plasma concentrations (PC) group of „difficult to treat patients“ remain a during multimedication. For further phar- challenge. Ribavirin (RBV) dose re- macokinetic studies, new HPLC-based commendations up to now are based on methods were developed in our laboratory body weight but RBV drug levels showed and evaluated for clinical use in 2005-2006 high interindividual fluctuation. RBV drug (Dr. W. Heinz). levels might play a crucial role not only in correlation to treatment effectiveness, but In addition to this scientific work in the also in avoiding deteriorating drug addicted laboratory, numerous clinical studies on the side effects such as haemolytic anemia. field of HIV-infection and chronic viral In this context individual therapy guidance hepatitis B and C were performed. using therapeutic drug monitoring (TDM) Studies to optimize the outcome of patients for RBV drug levels might play the crucial with different genotypes or patients with a role not only in correlation to treatment relapse or breakthrough of their hepatitis effectiveness but also in deteriorating drug C were done with different combination addicted side effects such as haemolytic therapy regimens consisting of interferon, anaemia in interferon-RBV combination ribavirin and amantadine. We participated regimens might proof as a suitable tool. phase II and III studies to assess effec- Using high pressure liquid chromato- tiveness and tolerance/side effects of graphic equipment, we developed a nucleoside analogues such as entecavir method for the detection of RBV (figure 1) and adefovir in chronic hepatitis B. in blood which should be evaluated to Concerning HIV, phase III studies on safety address the question whether standard and effectiveness of new HIV protease RBV dosing is inferior to RBV dose inhibitors (tipranavir and darunavir) and a adaptation guided by TDM. Another aims CCR5 co-receptor inhibitor were con- of this investigation are to evaluate prac- ducted. Moreover, clinical studies were ticability of RBV treatment in patients with started concerning the genetic background HIV-hepatitis co-infection as well as of nevirapine- toxicity and abacavir-hyper- hepatitis C and terminal renal insufficiency sensitivity. and to develop schemes for individualized For the last years we participated in the dose recommendations based on RBV NIH (National Institute of Health, Bethesda) drug levels and correlate these findings sponsored ESPRIT-study where long term with viral kinetics, different genotypes and efficacy of a cyclic IL-2 (interleukin 2) be able to enhance and eventually predict application on CD4 count in patients with therapy response. HIV is evaluated. In 2004, the SMART-study was started by Invasive fungal infections (IFI) are a life the National Institute of Allergy and Infec- threatening complication in patients with tious Diseases, Division of AIDS (NIAID) in

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Bethesda. The purpose of this study is to investigated for primary therapy or for the compare the long-term consequences of second line treatment of invasive asper- two strategies of antiretroviral manage- gillosis, as well as for the indication of ment: 1. a drug conservation strategy (DC), candidemia and invasive candidiasis. The- aimed at conserving drugs through epi- se clinical therapeutic trials are ac- sodic use of antiretroviral treatment for the companied and assisted by diagnostic minimum time to maintain CD4+ cell count research and surveys to the incidence of e“ 250 cells/µl, 2. the viral suppression fungal disease (Dr. W. Heinz). strategy (VS), a strategy aimed at sup- More detailed informations on clinical pressing viral load as much as possible, studies, main research projects and other immediately following randomization and activities are shown on the website of the throughout follow-up, irrespective of CD4+ division of infectious diseases. cell count. The section of infectious (www.medpoli.uni-wuerzburg.de/hepinf) diseases of the University of Würzburg is one out of nine selected centers in Ger- Activities many for this important study. Meanwhile, - „Chronische Virushepatitis – Update enrolment into the study was stopped in 2005“, January 26, 2005, organized by the January 2006 when it was found that the Medical Clinic II (director: Prof. Dr. H. VS strategy was superior to the DC strategy Einsele), Division of Hepatology and with regards to the primary endpoint Infectious Diseases by Prof. Dr. Hartwig (Opportunistic Disease (OD)/death), all- Klinker and Priv. Doz. Dr. P. Langmann. cause mortality, and serious adverse - „4. Würzburger Arzt-Patienten-Seminar: events. The essential results of SMART Chronische Virushepatitis“, April 16, 2005, were published in November 2006 (N Engl organized by the Medical Clinic II, Division J Med 2006; 355: 2283-2296). Gastroenterology/Hepatology and Hepato- Clinical studies in patients with haematology/Infectious Diseases by Prof. Dr. Micha- logical malignancies mainly focus on el Scheurlen and Prof. Dr. Hartwig Klinker. fungal infections. Due to different in- - „Chronische Virushepatitis – Update dications, underlying risk profiles and 2006“, January 25, 2006, organized by the timing of treatment, different compounds, Medical Clinic II, Division of Hepatology therapies and strategies are under in- and Infectious Diseases by Prof. Dr. Hart- vestigation in phase I, II and II trials. In wig Klinker and Priv. Doz. Dr. P. Langmann. patients with high risk of developing an - „Symposium 4. Würzburger Infektiologi- invasive fungal infection a new azole formu- sches Symposium – Virushepatitis und lation is examined for primary prophylaxis. HIV-Erkrankung“, April 01, 2006, organized The optimal timing for antifungal therapy in by the Medical Clinic II, Division of Infectious this risk population is matter of continuing Diseases by Prof. Dr. Hartwig Klinker and discussion, new drugs including third Priv. Doz. Dr. P. Langmann. generation azoles and echinocandins as -„Management der HIV-Exposition in Ge- well as lipid formulations of amphotericin burtshilfe und Pädiatrie“, May 03, 2006, April B allow earlier therapy with fewer side 01, 2006, organized by the Medical Clinic effects. Here a national trial investigates II, Division of Infectious Diseases by Prof. immediate versus deferred empirical Dr. Hartwig Klinker in cooperation with the antifungal treatment. In the same study, Universitäts-Kinderklinik (director: Prof. Dr. PCR for early diagnosis of invasive asper- C. P. Speer), Universitäts-Frauenklinik gillosis will be proven. As allogenic stem (director: Prof. Dr. J. Dietl) and Missions- cell transplantation and history of invasive ärztliche Klinik/Tropenmedizin (head: Priv. aspergillosis are both associated with a Doz. Dr. A. Stich) clearly increased risk of invasive fungal - „1. Würzburger Pilztagung“, July 12, 2006, infection, long term secondary prophylaxis organized by the Medical Clinic II (director: is tested. Another trial looks for the safety, Prof. Dr. H. Einsele), Division of Infectious tolerability and pharmacokinetic of an Diseases by Dr. Werner Heinz echinocandin, a liposomal polyene or the combination of both in stem cell transplant patients. In addition, echinocandins are

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3.9 Neurologische Klinik und Poliklinik und Institut für Neurobiologie

Education in regular State Schools and at the University of Munich Medical School, Gra- duation 1970, postdoctoral education and MD thesis (Dr.med.) at the Munich Medical School in Pediatrics and Pediatric Neurology; postdoctoral fellowship at the Neuromuscular Division at Johns Hopkins Medical Institutions, Baltimore,MD (Dr. D.B. Drachman) (1974 – 1976 ); further postdoctoral education in Neurology at the Technical University of Munich Medical School (1976 – 1978), Lecturer (1978 –1979)

Klaus Toyka Academic Posts: Associate (1979) and Full Professor (1981 -1989) at the University of 15. April 1945 Düsseldorf Medical School, Vice-Chairman, Head, Division of Neuroimmunology. Professor and Chairman at the University of Würzburg Medical School (1989 – present); Dean, School of Medicine (1996 – 1998); Vice-Dean (1998 – 2002); Acting Dean (2002); Assoc. Vice Dean (2005-present)

Several awards and named lectureships, organizer and co-organizer of international scientific meetings. Member of academic boards and societies including honorary memberships in the French, Belgian, and Polish Neurological Societies, in the Johns Hopkins Society of Scholars, and in the Royal College of Physician, London (FRCP by distinction); President of the European Neurological Society (2001 – 2002); Advisor and Consultant to several research organizations and to the pharmaceutical industry; board member on international advisory boards (Schering, Serono, Biogen Idec, Sanofi-Aventis, Teva, Medac)

Scientific publications: author and co-author of over 390 original publications with an emphasis on pathogenesis and treatment of neuromuscular disorders, multiple sclerosis, and immune mediated disorders including experimental studies using animal models of human diseases; author and contributor to books and book chapters, review articles in national and international periodicals.

A number of excellent scholars of the past 20 years have contributed to the scientific productivity of the former Division of Neuroimmunology at Düsseldorf and of the Würz- burg Department. Many of them have made a carrier as chairmen in Neurology and/or in the Neurosciences including Reinhard Hohlfeld (Munich), Hans-Peter Hartung (Düssel- Prof. Dr. Klaus V. Toyka, M.D., FRCP dorf), Heinz Reichmann (Dresden), Martin Koltzenburg (London,UK), Michael Sendtner Neurologische Klinik der (Würzburg), Georg Becker (Homburg), Ralf Gold (Bochum), Peter Rieckmann (Canada, UniversitŠt WŸrzburg in preparation). Josef Schneider Strasse 11 97080 WŸrzburg Hobbies: Classical music education in violin, emphasis on chamber music; mountain Tel.: ++49 (0)9 31 2 01-2 37 51 sports, cuisine with a personal cookbook co-authored by his wife Regine (4 editions in Fax: ++49 (0)9 31 2 01-2 39 46 German and 2 in English, first edition in Italian). [email protected]

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3.9 Department of Neurology gag was absent in unstimulated human cerebral and Institute of Neurobiology endothelial cell cultures, however, it became detectable after infection of cerebral endothelial Project: Expression of human endogenous cells with herpes simplex virus type-1 (HSV- retrovirus (HERV)-W in human cerebral 1). The transactivation of HERV-W proteins by endothelial cells and its role in the HSV-1 could enhance their potential oligo- pathogenesis of MS dendrotoxic and immunopathogenic effects, representing a mechanism Dr. Klemens Ruprecht (1,2), by which HSV-1, and possibly also other herpes Dr. Jürgen Schneider-Schaulis (3), viruses associated, could be linked to the Dr. Karola Obojes (1,3), pathogenesis of this disease. Dr. Herve Perron (4), Currently, cellular and humoral immune reactions Prof. Peter Rieckmann (1) against HERV-W gag protein are being investigated in MS patients and healthy controls. 1) Department of Neurology, Clinical research unit for multiple sclerosis and neuroimmunology Project: Anti EBV-specific, HLA-restricted 2) Department of Virology, University of T cells and their role in the pathogenesis of Saarland, Homburg multiple sclerosis 3) Department of Virology and Immuno- biology, Dr. Felix Gronen (1), 4) bioMerieux, R&D, Marcy L’Etoile, France Dr. Klemens Ruprecht (1,2), Dr. Benedikt Weissbrich (3), Multiple sclerosis (MS) is a frequently Dr. Erdwine Klinker (4), disabling inflammatory disease of the Dr. Harald H. Hofstetter (1), central nervous system which is thought Prof. Peter Rieckmann (1) to arise from a complex interplay between genetic and environmental factors. Among 1) Department of Neurology, Clinical environmental factors, (retro)viruses have Research Unit for Multiple Sclerosis and repeatedly been involved in the patho- Neuroimmunology genesis of MS, although none of the 2) Department of Virology, University of agents implcated so far has been shown Saarland, Homburg to play a unique causative role in this 3) Department of Virology and Immuno- disease. The multiple sclerosis - asso- biology ciated retroviral element (MSRV) is a 4) Department for Transfusion Medicine retroviral particle previously identified in cell and Immunohematology culture supernatants from patients with MS. Interestingly, MSRV has genetically The Epstein-Barr virus (EBV) has been homologous endogenous counterparts in implicated in the pathogenesis of multiple human DNA, the human endogenous sclerosis (MS), however, the mechanisms by retrovirus family type W (HERV-W). which EBV may be involved in MS are unknown. We have recently demonstrated promi- We here have investigated the frequency of nent expression of the MSRV/HERV-W gag EBV-specific cytotoxic T lymphocytes (CTL) in protein in brain endothelial cells of acute human leukocyte antigen (HLA)-B7+ patients or actively demyelinating chronic MS with MS and healthy controls using enzyme- lesions, a pattern not found in normal linked immunospot assays and seven previously controls. characterized HLA-B7-restricted immunogenic As retroviruses contain regulatory elements, EBV peptides. Overall, there were no significant which can by transactivated by other virus differences in the frequency of EBV-specific infections, we set up an in vitro model of cultured CTL between both groups. These data do not human cerebral endothelial cells to examine support the hypothesis that EBV could play a regulation and possible transactivation of HERV- role in MS by inducing EBV-specific CTL W gag by common viruses in this important responses in a quantitative manner. Other element of the blood brain barrier. In keeping pathogenic mechanisms involving EBV in the with the neuropathological findings, HERV-W pathogenesis of MS remain to be elucidated.

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Project: Molecular mechanisms of inter- Selected References: feron-β mediated antiviral defense - Perron H,, Lazarini F, Ruprecht K, P•choux- Longin C, Seilhean D, Sazdovitch V, Cr•ange Dr. Mathias Buttmann (1), A, Battail-Poirot N, Sibai G, Santoro L, Jolivet Dr. Friederike Berberich-Siebelt (2), M, Darlix JL, Rieckmann P, Arzberger T, Hauw JJ, Lassmann H. (2005) Human endogenous Prof. Edgar Serfling (2), retrovirus (HERV)-W env and gag proteins: Prof. Peter Rieckmann (1) physiological expression in human brain and 1) Department of Neurology, Clinical Re- physiopathological modulation in multiple search Unit for Multiple Sclerosis and sclerosis lesions. J. Neurovirol. 11: 23-33. Neuroimmunology 2) Department of Pathology, Section for - Kroner A, Rosche B, Kolb-MŠurer A, Kruse Molecular Pathology N, Toyka KV, Hemmer B, Rieckmann P, MŠurer M. (2005) Impact of the Asp299Gly poly- Most virus-infected cells release interferon- morphism in the toll-like receptor 4 (tlr-4) gene β (IFN-β) as a powerful inducer of antiviral on disease course of multiple sclerosis. J. defence. Endothelial cells tightly regulate Neuroimmunol. 165: 161-5. local immune cell recruitment by ex- - Ruprecht K, Obojes K, Wengel V, Gronen F, pression of adhesion molecules and Kim KS, Perron H, Schneider-Schaulies J, chemokines. Here, we studied the trans- Rieckmann P.(2006) Regulation of human criptional regulation of IFN-β-induced endogenous retrovirus-W protein expression chemokine expression in primary human by herpes simplex virus type 1: Implications β endothelial cells. IFN- increased mono- for the pathogenesis of multiple sclerosis. J. cyte chemoattractant protein-1/CCL2 Neurovirol. 12; 65-72. moderately and raised IFN-γ-inducible protein-10/CXCL10 mRNA steady-state - Gronen F, Ruprecht K, Weissbrich B, Klinker levels and protein release strongly, while E, Hofstetter H, Kroner A, Rieckmann P. (2006) no effect was detected on various other Frequency of HLA-B7-restricted Epstein -Barr chemokines. As shown by transient trans- virus-specific cytotoxic T lymphocytes in fections, induction of CXCL10 expression patients with multiple sclerosis. J. Neuro immunol. 180: 185-192 depends on an IFN-stimulated response element (ISRE) within the CXCL10 promoter. A double point mutation of the putative IFN regulatory factor (IRF)-1/2 binding site within this ISRE motif abolished IFN-β-induced promoter activity. In electrophoretic mobility shift assays, this ISRE motif showed a basal IRF-2 and an IFN-β-inducible IRF-1 and augmented IRF- 2 binding. Furthermore, stimulation with IFN-β induced a rapid nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2 and their transient binding to a g-activated site within the CCL2 promoter. The kinetics of transient STAT1 binding to this -activated site element correlated with the amount of Y701-phosphorylated nuclear STAT1, while S727-phosphorylated nuclear STAT1 re- mained stable over 24 h after stimulation. Therefore, IFN-β potently induces endothelial chemokine expression at the transcriptional level.

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Education and medical training: 1981-1982 „Studium generale“ at the University of Hamburg 1982-1988 Medical school at the Georg-August-Universität Göttingen 1988 Medical thesis: „Immunglobulin-producing cells in the cerebrospinal fluid“ (summa cum laude) 1995 Board certification: Neurology 1995 Habilitation thesis: Cytokine and adhesion molecules: activity parameters andtargets for immunomodulatory therapy of multiple sclerosis Chronology of clinical and academic positions: 1988-1989 Training in Neurology, Department of Neurology, University of Göttingen (Prof. Felgenhauer) 1989-1991 Post-doc-fellowship: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA (Dr. A.S. Fauci) Peter Rieckmann 1991-1995 Training in Neurology,Clinical Neurophysiology and Psychiatry at 23. Mai 1961 Department of Neurology, University of Göttingen (Prof. Felgenhauer) 1992-1995 Research group leader: Immunomodulation in the central nervous system, Department of Neurology, University of Göttingen (Prof. Felgenhauer) since 1996 Consultant and lecturer in Neurology, Department of Neurology, Univ. Würzburg (Prof. Toyka) since 1997 Research group leader: Clinical research unit for Multiple sclerosis and neuroimmunology 1992-1997 Gerhard-Hess-fellowship (German Research Association) since 2001 Associate Professor for Neurology Awards: 1994 Langheinrich-Prize for Multiple-Sclerosis-Research 1996 KŠte-Hammersen-Prize (German Multiple Sclerosis Society) 1996 Award of the medical faculty (University Gšttingen) for the best Habilitation thesis 1999 Hans-Heinrich-Queckenstedt-Prize 2000 Wartenberg-Lecture (German Neurological Association) Scientific publication: Over 150 original publication mainly on aspects of multiple sclerosis and blood brain barrier Membership in professional boards: Ethics Committee of the Medical Faculty, University of Würzburg European Committee for Trials and Research in MS (ECTRIMS) Medical Advisory Board of the MSIF Medical Advisory Board of the German MS Society (DMSG) Vice president of the Executive Board DMSG Prof. Dr. Peter Rieckmann Steering committees and advisory boards of various international multi-center clinical Neurologische Klinik der trials Universität Würzburg Co-Chairman of the International Multiple Sclerosis Therapy Consensus Group (MSTCG) Josef Schneider Strasse 11 Steering committees and advisory boards of various international multi-center clinical 97080 Würzburg trials Tel.: ++49 (0)9 31 2 01-2 37 51 Co-Chairman of the International Multiple Sclerosis Therapy Consensus Group (MSTCG) Fax: ++49 (0)9 31 2 01-2 3697 [email protected]

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3. 10 Universitäts-Kinderklinik Synovialgewebe produzieren verschiede- Pädiatrische Infektiologie ne entzündliche Botenstoffe. Die Produkti- on dieser proinflammatorischen Faktoren Interaktion von Borrelia burgdorferi, dem durch Synovialzellen als Reaktion auf das Erreger der Lyme Borreliose, mit huma- Vorhandensein von B. burgdorferi könnte nen synovialen Zellen (AG PD Dr. H. zu den typischen Symptomen von Arthritis Girschick, Dr. K. Latsch. Dr. S.K Singh, S. wie z.B. den Ergüssen beitragen (Singh Singh) and Girschick, 2004b) (Singh and Gir- schick, 2004a). Bis jetzt sind die Anfänge Die Lyme Arthritis ist durch eine starke ent- der Entzündung bei der Lyme Arthritis je- zündliche Reaktion vermutlich wegen des doch nicht im Detail untersucht worden. Es Vorhandenseins von Borrelia burgdorferi ist nicht bekannt, ob eine direkte Interakti- in dem betroffenen Gelenk gekennzeich- on von B. burgdorferi mit Synovialzellen ein net. Es wird vermutet, dass der Erreger di- entscheidender erster Schritt für die be- rekt eine Rolle in dem entzündlichen Ge- schriebene Kaskade von Entzündungsvor- schehen spielt. Proinflammatorische gängen sein kann. Auf der Basis dieser Effektorzellen des Immunsystems, wie Überlegungen wurden weiterführende Ex- Leukozyten und Lymphozyten wandern in perimente entworfen, in welchen Syno- das Synovialgewebe durch das Gefäß- vialzellen in der Zellkultur mit B. burgdorferi endothelium ein. In vielen Fällen sammeln Isolaten Geho und B31 exponiert wurden. sich die rekrutierten Lymphozyten in der Wie bereits im Vorbericht ausgeführt ha- Christian P. Speer entzündeten Synovia und bilden Lymph- ben wir mittels semiquantitativer RT-PCR 28. August 1952 follikel, auch Keimzentren genannt. Leu- die relative Chemokin mRNA Expression kozyten, Fibroblasten und andere Zellen im einer Vielzahl von Chemokinen, welche in

Academic career: 1971-1977 Medical School, Georg-August-University Göttingen 1976-1977 Practical Year, Department of Surgery, Internal Medicine and Department of Pediatrics, University of Göttingen 1977 Examen and Doctoral Thesis 1978-1986 Resident, Dept. of Pediatrics, University of Göttingen: General Pediatrics, Oncology, Endocrinology, Neuro-pediatrics, Intensive care, Neonatology 1982 -1983 Research Fellow: National Jewish Hospital and Research Center, Dept. of Pediatrics, Denver, Co., USA, Research grant from „Deutsche Forschungsgemeinschaft“ 1986 Thesis (Venia legendi), University of Göttingen Function in Societeies and Awards: 1987 Appointment as Associate Professor of Pediatrics, University of Göttingen 1993 – 1996 Secretary of the „European Working Group of Neonatology“, European Society of Pediatric Research 1994 Professor of Pediatrics, Director of the Department of Neonatology, University Children’s Hospital Tübingen Since 1994 Editor – „Zeitschrift für Geburtshilfe und Neonatologie“ 1996 Appointment as „Fellow of the Royal College of Physicians“, Edinburgh 1999 Professor of Pediatrics, Director of the University Children’s Hospital Würz- burg 1999 – 2004 Executive Board of the European Association of Perinatal Medicine 2000 – 2004 Peer Reviewer for Pediatrics, Deutsche Forschungs-gemeinschaft Prof. Dr. Christian P. Speer, FRCPE Since 2004 Editor in Chief „Biology of the Neonate“ Direktor der Univ.-Kinderklinik 2004 Appointment to the „Geoffrey-Thorburn Visiting Professor“ of the „Perinatal Josef-Schneider-Straße 2 Society of Australia and New Zealand“ 97080 Würzburg 2005 Invitation by the Hong Kong Pediatric Society to give the „James Hutchison’s Tel.: ++49 (0)931 -201-27830 Memorial Lecture 2005". Fax: ++49 (0)931 - 201 27833 2006 „Chiesi Award for Excellency in Neonatology 2006“ of the European [email protected] Association of Perinatal Medicine

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menschlichen Synovialzellen nach Expo- se zur Toll-like-Rezeptor-Interaktion von sition/Infektion mit Borrelia burgdorferi- menschlichen Synovialzellen mit Burg- Isolaten produziert werden, in vitro be- dorferi erarbeiten können. Hier zeigte sich, stimmt. Dies erfolgte mittels Immuno- dass die Oberflächenproteine C-defi- sorbant Assay (ELISA). Diese Ergebnisse zienten Stämme B31 und Geho ein sehr sind mittlerweile publiziert und zeigen, dass geringes Stimulationspotential gegenüber ein „Orchester“ von Chemokinen eine wich- den Synovialzellen aufweisen. Durch den tige Rolle in der Immunpathogenese von Einsatz von rekombinantem, lipidiertem früher Lyme-Arthritis spielen können, ins- Oberflächenprotein A und C konnte sie je- besondere konnten wir zeigen, dass die doch erstmals zeigen, dass gerade Chemokine MCP-2 in Ihrer Genexprression Synovialzellen, welche von Lymearthritis- ebenso wie MIP-1α induziert werden. Al- Patienten isoliert worden waren, be-son- lerdings war die letztendliche Chemo- ders empfindlich auf die Exposition mit kinkonzentration im Überstand suppri- OSP C reagierten. Hier konnte sie eine bis miert, was auf einen verstärkten RNA-Ab- zu 200-fach erhöhte Genexpression von bau hindeutet. Wir konnten zeigen, dass Toll-like-Rezeptor-2 nachweisen, welche in das Chemokin SDF-1 ein konstitutionell der Kontrolle und in der OSP A-exponier- exprimiertes Chemokin ist und dass die- ten Gruppe nicht nachweisbar war. Diese ses vor und nach Infektion mit Borrelia Arbeiten wurden auf dem diesjährigen burgdorferi in Synovialzellen konstant auf Kinderärztekongress der Deutschen Ge- Proteinebene exprimiert wird (Singh et al., sellschaft für Kinderheilkunde und Jugend- 2005). Bereits früher konnten wir zeigen, medizin mit dem 1. Posterpreis ausge- Hermann Girschick dass Metalloproteinasen und Cyclo- zeichnet. Somit scheint sich abzuzeichnen, Univ.-Kinderklinik oxygenasen in Synovialzellen verstärkt dass die komplexen Regulationsvorgänge Josef-Schneider-Straße 2 exprimiert werden und hier v. a. die auf der Ebene von Chemokinen, Zell- 97080 Würzburg Metalloproteinase 1 (Singh et al., 2004). adhäsionsmolekülen (Singh et al., 2006), Tel.: 0931 / 201-27830 Diese direkte proinflammatorische Reak- Metalloproteinasen und Cyclooxygenasen Fax: 0931 / 201 27833 tion, welche auch mit einer Induktion von in der Interaktion mit Toll-like-Rezeptor-2 [email protected] Cyclooxygenasen (COX-2) und entspre- ihren molekularen Ursprung haben. wuerzburg.de chender Postaglandin-Produktion einher- ging, haben wir mittlerweile in der Literatur Ein weiteres Feld in der Arbeitsgruppe Priv.- berichtet (Singh et al., 2004). Da bisher Doz. Dr. H. Girschick ist die Evaluation chro- nicht klar war wie die komplexe Interaktion nisch-nicht bakterieller Osteomyelitiden im von Borrelia burgdorferi mit dem mensch- Kindesalter in welchem Rahmen wir un- lichen Wirt auf molekularer Ebene abläuft, sere Langzeitverlaufsergebnisse nun be- erschien es nahe liegend, dass ins-beson- richten konnten (Girschick et al., 2005). Die dere das sog. Toll-like-Rezeptor-System Erkrankung Hypophophatasie ist bereits eine entscheidende Rolle spielen könnte. seit Jahren ein klinischer Schwerpunkt von Hier ist anzumerken, dass gerade der Toll- PD Dr. Girschick. Hier konnte nun in Zu- like-Rezeptor 2 durch die Erkennung von sammenarbeit mit dem Institut für Hygie- Lipoproteinen ein wichtiger primärer Re- ne und Mikrobiologie die molekulare Ana- zeptor für die Erkennung von Borrelia lyse des Biofilms von Zähnen der betroffe- burgdorferi sein könnte. Borrelia burg- nen Kinder berichtet werden. Kindern mit dorferi exprimiert keine Lipopolysaccharide Hypophosphatasie fallen die Zähne vorzei- auf seiner Oberfläche, dafür aber eine Viel- tig aus, so dass die Frage bestand, in wie zahl von Lipoproteinen. Gerade letztere weit ein besonders aggressives Keim- werden von Toll-like-Rezeptor 2 in Verbin- gemisch bestehen könnte. Wir konnten dung mit Toll-like-Rezeptor 1 möglicher- jedoch zeigen, dass der Biofilm vergleich- weise erkannt. Ein weiteres Molekül was bar ist mit einer gesunden Population erkannt werden kann, ist das Geisel-Anti- (Valenza et al., 2006). Interessante Fall- gen durch den Toll-like-Rezeptor 5. Um berichte zu infektiologischen Themen wur- hier Studien vorzubereiten haben wir eine den im Berichtszeitraum erstellt (Kunz- Übersichtsarbeit zu diesem Thema ge- mann et al., 2005) (Klotz et al., 2006). schrieben (Singh and Girschick, 2006) und Frau Dr. Latsch hat bereits erste Ergebnis-

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Modifizierung pulmonaler remodelling Pro- sätzlich zeigte sich eine Erhöhung des zesse durch pränatale Infektionen proinflammatorischen Zytokins TNF-α in (AG Prof. Dr. C. P. Speer, PD Dr. B. W. der Lunge. Kramer, Dr. S. Kunzmann) Chorioamnionitis führt zu einer systemischen und lokalen, pulmonalen Ent- Die bonchopulmonale Dysplasie (BPD) zündungsreaktion. Dabei wird TGF-β1 ver- des Frühgeborenen ist durch eine Störung mehrt in der Lunge synthetisiert. Dies führt der normalen Lungenalveolisation und - zum einen zu einer Inhibition der norma- vaskulation charakterisiert. Transforming len Lungenalveolarisation, zum anderen zu growth factor beta (TGF-β) spielt dabei so- einer Suppression der Entzündungs- wohl eine wichtige Rolle in der normalen reaktion in der Lunge. Daneben wirkt Lungenentwicklung und der pulmonalen TGF-β1 auf die Wundheilungsprozesse im Inflammationsregulation, als auch bei pul- Lungenbindegewebe (airway remodelling), monalen remodelling-Prozessen. Con- was bei repetitive Schädigung zu fibro-ti- nective tissue growth factor (CTGF) fungiert schen Umbauprozessen in der Lunge füh- hierbei als downstream Mediator von ren kann. Das gleichzeitig erhöhte TGF-β und beeinflusst die Integrität und TNF-β in der Lunge verhindert die Indukti- Stabilität der extrazellulären Matrix. Zusätz- on von CTGF durch TGF-β1. Hierdurch wird lich födert CTGF die Angiogenese und das zum einen der physiologische Heilungs- vascular remodelling. In einem Tiermodel prozess im Lungenbindegewebe gestört, für Chorioamnionitis sollte die Regulation zum anderen jedoch auch das Ausmaß der von TGF-β und CTGF in der Lunge unter- fibrotische Umbauprozess in Lunge ver- sucht werden. Chorioamnionitis ist mit mindert, was typisch für die histologische Frühgeburtlichkeit und Veränderung der Form der BPD ist. Zum anderen könnte die Lungenarchitektur und der Lungengefäße Herunterregulation von CTGF die normale assoziiert, die vergleichbar mit denen bei Lungenendothelzell-Funktion, sowie die der BPD von Frühgeborenen sind. Entwicklung und die Regeneration von Hierfür wurden die Lunge von frühge- Endothelzellen beeinflussen. borenen Schafe mit einem Gestationsalter von 125 Tagen 5 h, 24 h, 72 h und 7 Tage nach Endotoxin-Injektion (4 mg) in das Fruchtwasser auf die Expression von TGF-β und CTGF mittels RT-PCR auf mRNA 3.10 Children Hospital - und mittels Western Blot und Immun- Paedriatic Infectiology histochemie auf Protein hin untersucht. Eine Aktivierung des durch TGF-b indu- Interaction of Borrelia burgdorferi, the Lyme zierten Smad-Signaltransduktionsweges disease spirochete, with human synovial in der Lunge wurde durch den spezifischen cells (AG PD Dr. H. Girschick Dr. K. Latsch. immunhistochemischen Nachweis von Dr. S.K Singh, S. Singh) phosphorylierten Smad2 untersucht. Für TGF-β zeigte sich im Vergleich zur Lyme arthritis is characterized by a strong Kontrollgruppe eine zeitabhängige Zunah- inflammation in the affected joint. There are me der Expression sowohl für mRNA, als reports that the Lyme disease spirochete auch für Protein. Parallel dazu konnte auch Borrelia burgdorferi is present in the joints eine Phosphorylierung des Signaltrans- and is contributing directly to the in- duktionsproteins Smad2 und somit eine flammation. Proinflammatory cellular Aktivierung des Smad-Signaltransduk- components of the immune system are tionsweges im Lungengewebe festgestellt being recruted to the joint. Lymphocytes are werden. Für CTGF zeigte sich immun- forming lympoid follicles or germinal histochemisch eine spezifische Expressi- centers. Leukocytes and fibroblasts lo- on in Lungenendothelzellen. In diesen cated in the joint are producing a variety of wurden 7 d nach Endotoxin-Applikation molecules involved in chemotaxis (chemo- CTGF deutlich vermindert exprimiert. Die- kines), adhesion (cell adhesion molecules se Verminderung von CTGF konnte auch CAMs), tissue destruction (matrix metallo- auf mRNA Ebene bestätigt werden. Zu- proteinases MMP), and pain and in-

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flammation (cyclooxigenases COXs). bacterial colonization of the oral cavity in Synovial cells are specialized fibroblasts hypophosphatasia patients. A few clinical capable of producing the just mentioned case reports have been published molecules. Synovial cell activation could regarding rare aspects of infectious contribute significantly to the inflammatory diseases. reaction. In a coculture system using Borrelia burgdorferi together with synovial cells we could demonstrate, that the Antenatal inflammation induced TGF-β1 chemokine MCP-2 in addition to MIP-1β but suppressed CTGF in preterm lungs was strongly induced regarding the gene (AG Prof. Dr. C. P. Speer, PD Dr. B. Kramer, expression, however, the chemokine Dr. S. Kunzmann) concentration in the supernatant was suppressed. This suggested a high RNA Chorioamnionitis is frequently associated degradation in those activated synovial with preterm birth and increases the risk of cells. In addition, the chemokine SDF-1 adverse outcomes such as broncho- was constitutively expressed. As we have pulmonary dysplasia (BPD). Transforming shown before the expression of MMP-1 growth factor (TGF)-β1 is a key regulator of was induced in synovial cells exposed to lung development, airway remodelling, lung Borrelia burgdorferi. In addition, COX-2 fibrosis and regulation of inflammation, gene expression was also induced. So far, and all these processes contribute to the it was not clear how this complex interaction development of BPD. Connective tissue of Borrelia burgdorferi and the human host growth factor (CTGF) is a down-stream is determined on molecular level. We were mediator of some of the pro-fibrotic effects considering the Toll-like-receptor system of TGF-β1, of vascular remodelling and of to play a role since it is known that Toll-like- angiogenesis. TGF-β1 induced CTGF receptor 2 is a major receptor for lipo- expression can be blocked by tumor proteins expressed by Borrelia burgdorferi. necrosis factor (TNF)-β. We asked if This bacteria does not express lipo- chorioamnionitis associated antenatal polysaccharides therefore lipoproteins are inflammation would regulate TGF-β1, the the targets of interaction. We have gathered TGF-β1 signalling pathway and CTGF in preliminary results showing that the outer- preterm lamb lungs. Fetal sheep were surface protein (OSP) C is able to signi- exposed to 4 mg intra-amniotic endotoxin ficantly stimulate synovial cells resulting in or saline for 5 h, 24 h, 72 h or 7 days before a tremendous 200-fold elevation of the gene preterm delivery at 125 days gestation age expression of toll-like-receptor 2. This effect (term is 150 days). Intra-amniotic endotoxin was not seen with recombinant OSP A. increased lung TGF-β1 mRNA and protein Using Borrelia burgdorferi strains ex- expression. Elevated TGF-β1 levels were pressing OSP C in low or non-existing associated with a TGF-β1-induced phos- amounts we also could show that no phorylation of Smad2. CTGF was se- stimulation of toll-like-receptor 2 mRNA lectively expressed in lung endothelial cells resulted after exposure. Thus, we will in control lungs and intra-amniotic endo- conduct further experiments with gene- toxin caused CTGF expression to decrease tically altered borrelia strains or human to 30% of control values and isolates expressing OSP C in a significant TNF-β protein to increase. The antenatal amount. Our results demonstrated a inflammation induced TGF-β1 expression complex interaction of Borrelia burgdorferi and Smad signalling in the fetal lamb lung with human synovial cells. The differential may contribute to impaired lung alveo- expression of chemokines, MMPs, COXs larization and to reduced lung inflammation. and especially Toll-like receptors in synovial Decreased CTGF expression may inhibit cells could be essential triggers in the vascular development or remodelling and generation of Lyme arthritis. limit lung fibrosis during remodelling. The- In addition to this basic science project, se effects may contribute to the impaired the group of H. Girschick also worked on alveolar and pulmonary vascular develop- the evaluation of chronic non-bacterial ment that is the hallmark of the histologic osteomyelitis in childhood in addition to the form of BPD.

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3.11 Klinik und Poliklinik für 3.11 Department of Skin Di- Haut- und Geschlechtskrank- seases and Veneral Diseases heiten

Zusammenfassung Summary

Zur Auslösung einer spezifischen Immun- To resist microbial infection, the host has antwort gegen Mikroorganismen sind den- developed plenty of defence mechanisms dritische Zellen (DZ) als Bindeglied zwi- of the innate and adaptive immune system. schen angeborener und erworbener Im- Dendritic cells (DCs) provide the link munität von grundlegender Bedeutung. Die between these arms of immunity. The Auseinandersetzung der DZ mit Pathoge- initiation of an immune response is nen bestimmt maßgeblich den weiteren critically dependent on the activation of Verlauf einer Infektion. DZ sind in der Lage, these cells. DCs can discriminate between zwischen verschiedenen Mikroorganis- different classes of microorganisms and men zu unterscheiden und eine maßge- elicit tailored antimicrobial immune re- schneiderte antimikrobielle Immunantwort sponses. They have an extraordinary zu initiieren. Auf der anderen Seite können capacity to stimulate naïve Pathogene jedoch auch mit der Funktion T cells and initiate primary immune re- dendritischer Zellen interferieren und da- sponses. In turn, some pathogens interfere mit ihre Elimination verzögern oder verhin- with DC function to block or delay their dern. Untersuchungen humaner DZ und elimination by the host. Progress in ihrer Vorläuferzellen in der Interaktion mit understanding the role of DCs in the unterschiedlichen intra- und extrazellulä- response to microbes discloses patho- ren Pathogenen können grundlegende genesis of microorganisms. Einblicke in die Pathogenese geben.

Eva-B. Bröcker Projects: 1. Juni 1946 The reported projects were performed in cooperation with Prof. M. Frosch / Dr. O. Kurzai, Institute of Hygiene and Mikrobiology University of Würzburg.

Academic education: 1965-1971 Studies of Medical Scienes at the Universities of Kiel (Germany) and Leeds (UK) 1972 Graduation (Dr. med.) 1973 MD-License (Kiel, Germany) 1973-1975 DFG-Scholarship for Immunology, Kiel (Germany) Guest researcher at the Basel, Institute for Immunology (CH) 1975 Training of Dermatology at the University of Münster (Germany) 1982 Admission as a Doctor of Dermatology and Venerology 1984 Habilitation for Dermatology and Venerology 1986 Nomination as Professor for Dermatology (Münster) 1986 Authority to bear the additional designation „Allergology“ Prof. Dr. E.-B. Bröcker since1992 Director of the Dept. of Dermatology, University Würzburg Klinik und Poliklinik für Dermatologie, 1996-2005 Authority to bear the additional designations „Phlebology, Environmental Venerologie und Allergologie der Medicine, Dermatophatology“ Universität Würzburg Functions and Awards (selected): Josef-Schneider-Str. 2, Bau D8, Editor of Dermatological Journals 97080 Würzburg Johannes Fabry Medaille (1989) Tel.: 0931-201-26351 Bayer. Maximiliansorden 2001 Fax: 0931-201-26462 Braun Falco Medaille 2006 [email protected]

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PD Dr. med. Dr. rer. nat. Annette Kolb-Mäurer for IL1-beta, IL-6, IL-8, IL-12p40, TNF-alpha, IFN-gamma and GM-CSF. However, 1. Morphological plasticity of Candida significantly lower levels of the regulatory albicans is a major virulence factor. Using mediator IL-10 were induced by en- pH-dependent dimorphism we show, that capsulated strains in comparison to human Dendritic Cells recognize fila- isogenic unencapsulated derivatives. The mentous forms and blastoconidia of a vi- use of truncated LPS isoforms in vaccine rulent C. albicans isolate (strain SC5314). preparations can therefore not only result Heat inactivated and viable blastoconidia in attenuation but also in more efficient are rapidly phagocytosed by human DC. targeting of DC. Further resolving this still However, viable yeast cells start to filament miscellaneous interaction will promote our inside the DC at later stages of infection, understanding of N. meningitidis virulence leading to penetration and loss of cellular and contribute to a rationale approach for integrity. The cytokine burst of human DC designing a vaccine against serogroup B induced upon contact with Candida is meningococci. dominated by the granulocyte activating, chemotactic factor IL-8 and the proinflammatory mediator TNF-α. Blastoconidia induce markedly lower cytokine levels than filamentous forms. Whereas IL-8 secretion is mainly cell mass dependent, release of TNF-α a major proinflammatory cytokine, is clearly dependent on the morphology of Candida. Taken together, these data show, that morphological plasticity of C. albicans is of major importance in the interaction with human DC, but does most likely not affect the IL-12 secretion of human DC. En- gagement of environmentally regulated dimorphism will enable the use of isogenic strains for defining morphology-related effects in future.

2. Meningococcal lipopolysaccharide is of crucial importance for the pathogenesis of Selected references: invasive infection. We show, that sialylation - Kurzai O, Schmitt C, Claus H, Vogel U, Frosch and elongation of the alpha-chain effectively M, Kolb-Maurer A. Carbohydrate composition shields unencapsulated viable Neisseria of meningococcal lipopolysaccharide modu- meningitidis from recognition by human lates the interaction of Neisseria meningitidis dendritic cells. In contrast, beta- and with human dendritic cells Cell Micro-biol. gamma-chain of the LPS carbohydrate 2005;7:1319-34 moiety play only a minor role in the - Kurzai O, Schmitt C. Brocker E, Frosch M, interaction with DC. The protective function Kolb-Maurer A. Polymorphism of Candida of the LPS carbohydrate moiety for the albicans is a major factor in the interaction bacteria can be counteracted in vivo by with human dendritic cells Int J Med Micro- phase variation of the lgtA gene encoding biol. 2005; 295:121-7 LPS glycosyltransferase A. Capsule ex- - Schoen C, Kolb-Maurer A,Geginat G, Loffler D, Bergmann B, Stritzker J, Szalay AA, Pilgrim pression protects N. meningitidis efficiently S, Goebel W. Bacterial delivery of functional from recognition and phagocytosis by DC messenger RNA to mammalian cells Cell independent of the LPS structure. Despite Microbiol. 2005;7:709-24 the significant impact of LPS structure on - Schmidt E, Weissbrich B, Brocker EB, the adhesion and phagocytosis of Fleischer K, Goebeler M, Stich A. Orf followed N. meningitidis no differences were found by erythema multiforme J Eur Acad Dermatol in terms of cytokine levels secreted by DC VEnereol. 2006;20: 612-603

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3.12 Chirurgische Klinik und modell getestet. Beim Vergleich der Poliklinik Immunreaktivität von Seren aus Patienten vor und während einer Staphylokokken- Entwicklung humaner monoklonaler Anti- infektion wurde u.a. ein als IsaA bezeich- körper als neue Therapie von chirurgischen netes Antigen gefunden und für Immuni- Infektionen, verursacht durch methicillin- sierungen rekombinant hergestellt. Ein resistente und methicillin-sensible Sta- monoklonaler IgG2a Maus-Antikörper ge- phylococcus aureus (MRSA und MSSA) gen IsaA konnte die Besiedlung von S. aureus in einem Maus-Katheter-Modell si- Zusammenfassung gnifikant verringern. In weiteren Versuchen wird gegenwärtig die Wirksamkeit von wei- Im Rahmen des bearbeiteten Projektes teren spezifischen monoklonalen Antikör- sollen humane, monoklonale Antikörper für pern getestet. Genetische Untersuchungen die Therapie von Infektionen durch Sta- zur Regulation der isaA-Expression zeig- phylococcus aureus entwickelt werden. ten, dass die Produktion dieses Proteins Dazu wurden immundominante Antigene von globalen Virulenzregulatoren wie sarA von S. aureus identifiziert, charakterisiert und sigB kontrolliert wird. Eine spezifische und spezifische Mutanten im Kleintier- SigB-Mutante war im Maus-Kathetermodell Arnulf Thiede 20. August 1942 1949-1958 primary and secondary school in Kiel 1958-1962 study of medicine at Kiel, Berlin, Frankfurt, Tübingen 1968-1969 house officer time in Berlin, Kiel, promotion and dissertation as Dr. med. 1970 surgical residency program in Kiel (until 1987) 1972 foundation of a microsurgical laboratory for experimental transplantation research and microsurgical research 1973-1987 project leader in various surgical transplantation research programs supported by Sonderforschungsbereich 111 of DFG (German research council) 1976 habilitation for university lecturer, consultant, department of general surgery University of Kiel 1976 Langenbeck award of the German society of surgery 1979 foundation of the transplant center Kiel 1980 associate professor of surgery 1975,79, study visits in USA (3 x), Great Britain (2 x) 1981,84,88 Thailand (2 x) 1983 head consultant department of general surgery university of Kiel 1985 continuous referee of the DFG (German research council); German ministery of education, science, research and technology (BMBF); second director department of general surgery university of Kiel 1987 visiting professor Jichi University, Japan 1988 medical director of the surgical clinic of Friedrich Ebert Hospital, Neumünster, Germany 1988/89 member of the commission of the German health authority for suture materials: new edition of the European pharmacopoe 1991 director of the department of surgery of the university of Würzburg, Germany Prof. Dr. med. Arnulf Thiede 1994/96 visiting professor in Curitiba, Brasil Universitätsklinikum Würzburg 1996 chairman of the Bavarian surgical society Chirurgische Klinik und Pöliklinik 1996/97 chairman of the surgical research groups in the interdisciplinary center Zentrum Operative Medizin for clinical research (IZKF) of the Julius-Maximilians-Universität Würzburg Oberdürrbacher Str. 6 2000/2001 president of the German Society of wound healing D-97080 Würzburg up to now more than 400 publication in clinical and experimental surgery in national and Tel.: ++49 (0)931-201-31000 international books and journals Fax: ++49 (0)931-201-31009 [email protected]

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deutlich attenuiert. Alle bisherigen Daten tiert. Über diesen venösen Zugang werden unterstreichen die Bedeutung einer effek- 107 S. aureus-Zellen inokuliert, von denen tiven Wirts-Immunreaktion gegen IsaA für einige an der Katheterwand adherieren, eine Abwehr von S. aureus. einen Biofilm bilden und von dort in das Gewebe dissiminieren. Bei diesen Abläu- 1) Analyse von Zielstrukturen für humane fen sind verschiedene Virulenzfaktoren in- monoklonale Antikörper volviert und das Geschehen spiegelt sehr gut pathophysiologische Prozesse bei Es wurde nach immunodominanten Anti- nosokomialen Infektionen wieder. In einem genen gesucht, die als potenzielle Target- ersten Versuchsansatz wurden ein biofilm- struktur für eine Immunotherapie geeignet bildender S. aureus Stamm und dessen sein könnten. Dazu wurden zwei Ansätze isogene SigB-Mutante eingesetzt. Sigma angewendet (i) Screening von Patienten- B ist ein alternativer Sigma-Faktor, der auch seren mit Reaktivität gegen S.aureus-spe- an der Regulation der IsaA-Expression zifische Faktoren und (ii) Expression von beteiligt ist. Nach 120 h wurde die Bak- Staphylokokkenproteinen in einer Ex- terienlast in den Organen und in dem Ka- pressionsgenbank. theter bestimmt und die Biofilmbildung durch Elektronenmikroskopie untersucht. 2) Untersuchungen von Staphylokokken- Der Wildtypstamm konnte signifikant häu- Udo Lorenz 7. Juli 1969 mutanten in Kleintiermodellen figer aus den einzelnen Organsystemen isoliert werden als der Mutantenstamm In diesem Teil des Projektes wurde die in- und es konnte somit eindeutig die einge- vivo Bedeutung von identifizierten immuno- schränkte Virulenz der SigB-Mutante ge- dominanten Proteinen für die Entstehung zeigt werden. In einem zweiten Tiermodell und Ausbreitung einer Infektion studiert. kann mit Hilfe eines biolumineszierenden Dafür wurden die Gene isaA, isaB und sigB S. aureus Stammes die Dynamik des mutagenisiert. Diese Gene kodieren für Infektionsprozesses visualisiert werden. In immunodominante Zellkomponenten von diesem Weichteil-Infektionsmodell wurden S. aureus (IsaA, IsaB) oder sind an der verschiedene Mutanten und therapeuti- Regulation dieser Faktoren beteiligt (SigB). sche monoklonale Antikörper getestet. In Es wurde ein Tiermodell entwickelt, das Fig.1 ist der abgeschwächte Infektions- die Analyse pathophysiologischer Prozes- verlauf einer IsaA Insertionsmutante oder se bei typischen S. aureus-Infektioen er- nach Gabe eines anti-IsaA Antikörpers laubt. In diesem Modell wird einer Maus (MAB-ISAA29) gargestellt. ein Katheter in die Vena jugularis implan-

Education: 1976 – 1988 Gymnasium, Berlin/ Germany 1988 Abitur (roughly equivalent to A levels) 1990 – 1995 Ernst-Moritz-ArndtUniversity,Greifswald/ Germany Study of Human Medicine state examination 1996 medical degree from the University of Greifswald/ Germany Work Experience: 1990 preclinical year, Charité, Berlin/ Germany 1995 – 1996 practical year, Department of Surgery, University of Southern California, Los Angeles/ USA, Department of Vascular Surgery, Albert Einstein Dr. Udo Lorenz College of Medicine and Montefiore Medical Center, New York/ USA, Universitätsklinikum Würzburg University of Nebraska, Omaha/ USA Chirurgische Klinik und Pöliklinik 1996 – 1998 first year resident, Department of General Surgery, University of Würzburg/ Zentrum Operative Medizin Germany Oberdürrbacher Str. 6 1998 – 1999 scientific assistant, Institute for Molecular Infection Biology, D-97080 Würzburg University of Würzburg/ Germany Tel.: ++49 (0)931-201-31000 since 1999 resident, Department of General Surgery, University of Würzburg/ Germany Fax: ++49 (0)931-201-31009 [email protected]

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3) Passive Immunisierung im Maus- significantly reduce the settlement of S. Kathetermodell aureus in organs in a catheter-sepsis model. In further tests, the effectiveness of Mit Hilfe des Maus-Kathetermodells und different specific monclonal antibodies des Biolumineszenz-Modells soll geprüft should be presented. Genetic exami- werden, inwieweit monoklonale Antikörper nations to the regulation showed that the allein oder in Kombination in der Lage sind production of IsaA is controlled by global einen Immunschutz zu induzieren. virulence regulators like sarA and sigB. A Ein monoklonaler Antikörper wurde gegen specific SigB-mutant was considerably das IsaA-Protein generiert und in einem attenuated in the mouse catheter model. Ratten-Infektionsmodell getestet. Es zeig- All previous data underline the significance te sich, dass eine Anti-IsaA Ak-Gabe die of an effective host immune response Infektion mit S. aureus zurückdrängen against IsaA for a defence of S. aureus. kann. Dieser Effekt wurde durch eine be- schleunigte Phagozytose durch humane 1)Analysis of target structures of Staphylo- polymorphkernige Granulozyten und durch coccus aureus for the development of hu- eine direkte Blockierung von IsaA erreicht. man monoclonal antibodies Die Blockierung von IsaA, einer lytischen Transglykosylase, führt wahrscheinlich zu Putative immunodominant antigens were einer gestörten Zellwandsynthese von S. investigated in order to evaluate whether aureus. or not these antigens can be used as targets for the development of immuno- 4) „knock out“ Strategie im Maus-Katheter- therapeutics. Two approaches have been modell applied: (i) Screening of sera of patients and identification of immunodominant In diesem Teilprojekt sollen verschiedene antigenic factors of Staphylococcus aureus humane, wirtsspezifische Faktoren und (ii) Construction of an expression library of deren Einfluß für den Infektionsverlauf mit S. aureus proteins. S. aureus untersucht werden. Durch ge- zielte Inaktivierung von Genen, zum Bei- 2) Investigation of mutants of Staphylo- spiel knock-out für Plasmafibrinogen in coccus aureus in experimental models Mäusen, lässt sich der Effekt im Katheter- Sepsis-Modell studieren. This project part aims at investigating the role of different immunodominant antigens in-vivo. For this purpose several deletion mutants were constructed including muta- 3.12 Surgical Clinic with Out- tions of isaA, isaB and sigB. These genes patients’ Department were identified either as important immunodominant antigens (IsaA, IsaB) or Summary may play a major role in the regulation of virulence-associated genes. In the context of the project, human Moreover, a catheter-related infection monoclonal antibodies shall be developed model in mouse was developed which for the therapy of serious infections caused allows the analysis of pathophysiological by Staphylococcus aureus. Immuno-domi- processes typical seen during invasive S. nant antigens of S. aureus were identified, aureus infections. In this model system, a characterized and specific mutants tested catheter was implanted into the jugular vein in a small animal model. At the comparison of mice. Following implantation S. aureus of the immunoreactivity of sera from bacteria were given via the catheter forming patients before and during a staphylo- a strong biofilm inside the lumen of the coccus infection an antigen described as catheter. Some bacteria can afterwards IsaA was found and produced recom- leave the biofilm and disseminate into binantly for immunizations. A monoclonal several organs forming multiple abs- IgG2a mouse antibody against IsaA could cesses. Several virulence factors are

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involved in the pathogenesis of catheter- 3) Passive immunization studies related infections. In a first attempt, the role of the alternative sigma factor SigB during With the help of the mouse catheter model pathogenesis of catheter-related infections and the bioluminescence model it shall be was investigated using the animal model. checked how far monoclonal antibodies The biofilm-forming wildtype strain and its alone or into combination are able to induce isogenic mutant was applicated via the an immune protection. A monoclonal implanted catheter and the outcome of the antibody was generated against the IsaA infection was determined 120 h after protein and tested in a mouse infection infection. The number of bacteria in the model. MAB-ISAA29 enhances significant organs was investigated using quantitati- S. aureus containment in antibody treated ve plate counting. These experiments mice compared to control mice. turned out that the SigB wildtype was The proposed action of MAB-ISAA29 is significantly more virulent than its isogenic evoked by antibody-mediated phago- mutant suggesting a pivotal role of SigB cytosis and by preventing the completion during the infection process. Further of the nascent cell wall of S. aureus. studies are under way to investigate the role of IsaA and IsaB in the infection 4) „ knock out„ strategy in the mouse process. In a second animal model, catheter model bioluminescent S. aureus were used to visualize the dynamics of the infection In this partial project different humane, host process. In this soft tissue infection model specific factors and their influence shall be different mutants and therapeutic mono- examined for the infection course with S. clonal antibodies will be tested. The aureus. By a specific inactivation of genes, impaired course of infection of an IsaA for example knock out for plasma-fibrino- insertion mutant and after anti IsaA antigen in mice, the effect can be studied in body treatment (MAB-ISAA29) is displayed the catheter sepsis model. in Figure 1.

Fig. 1: Soft tissue infection model. Explanation, see point 2) in the text.

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3.13 Die Tropenmedizinische Abteilung der Missionsärzt- lung der Missionsärztlichen Klinik in enger lichen Klinik Kooperation mit den Arbeitsgruppen des Missionsärztlichen Instituts Würzburg bege- Weltweit, aber auch in Deutschland spie- ben. In den vergangenen zehn Jahren wur- len tropenmedizinische Problemfelder den zahlreiche Unterrichtseinheiten zu ver- eine zunehmende Rolle. Gesundheits- schiedenen Themenstellungen und für ganz dienste, die mit tropischen Infektions- verschiedene Zielgruppen organisiert. Das krankheiten konfrontiert werden, sind oft- Spektrum reicht von Kursen über den Ein- mals schnell überfordert, worunter die Ver- satz angepasster Labormethoden in Ge- sorgung von Patienten leidet. Die medizi- sundheitseinrichtungen des ländlichen Afri- nische Forschung im klassischen Sinn ka, die Einführung der Ultraschalldiagnostik verfolgt den Ansatz, grundlagenwissen- in Innerer Medizin und Geburtshilfe in afrika- schaftliche Erkenntnisse über die Erreger nischen Distriktkrankenhäusern, der Unter- zu gewinnen, die Pathophysiologie der Er- weisung ausreisender Entwicklungshelfer krankungen zu verstehen oder theoreti- über die medizinischen Realitäten in ihrem sche Ansätze für neue Wirkstoffe und Gastland oder eine Internet-basierte inter- Therapiekonzepte zu entwickeln. Eine an- aktive Lerneinheit zum Thema HIV/AIDS bis dere Möglichkeit, auf die Herausforderun- hin zu einem Kursus über das Management gen der Tropenmedizin zu reagieren, be- hochkontagiöser Erkrankungen in Deutsch- steht in dem Versuch medizinisches, pfle- land, der in Zusammenarbeit mit dem Ro- gerisches und labortechnisches Personal bert-Koch-Institut inzwischen regelmäßig in der Versorgung von Patienten und in der durchgeführt wird. In den vergangenen zehn optimalen Ausnutzung der vorhandenen Jahren wurden über 3000 Angehörige von Ressourcen zu unterrichten. Medizinberufen über diese Ausbildungs- In genau dieses Feld hat sich in den letz- einheiten erreicht. In diese Zahl nicht mit ein- August Stich ten Jahren die Tropenmedizinische Abtei- gerechnet sind Vorlesungen und medizini- 09. September 1960 Academic Career: 1978-1985 Studies of Medicine at the Universtiy of Wuerzburg 1986 PhD in ophthalmology 1985-1991 Medical training and Announcement to an ophthalmology 1988 Development aid in Zimbabwe 1991-1993 Postgradual Study in London, Master of Science in Clinical Tropical Medicine 1993 Application in Somalia 1994-1995 Projekt leader of an development aid programme for Médecins sans Frontières in Kambodscha 1996 Additional education Tropical Medicin 1995-1999 Medical Training to an Internist 1999-2001 Research fellow at the Department of Parasitology of the University Heidelberg since 2001 Project group leader „Klinische Tropenmedizin am Missionsärztlichen Institut“ Würzburg since 2004 Head of Department „Klinische Tropenmedizin am Missionsärztlichen Institut“ Würzburg Functions and Awards: PD Dr. med. August Stich 1992 Duncan-Award of the DTM&H-course of the Royal College of Physicians Missionsärztliches Institut 1992 Frederick Murgatroyd Award of London School of Hygiene and Tropical Arbeitsgruppe Tropenmedizin und Medicine Seuchenbekämpfung since 1996 Local Secretary of the Royal Society of Tropical Medicine and Hygiene für Hermann-Schell-Str. 7 Deutschland 97074 Würzburg 1997-2000 Member of the Organizing commitee „Ärzte ohne Grenzen“ (Friedensnobel Tel.: 0931 - 80 48 523 preis 1999) Fax: 0931 - 80 48 530 since2002 Member of „Leitlinienausschuss der Deutschen Gesellschaft für Tropen [email protected] medizin und Internationale Gesundheit“

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schen Weiterbildungsveranstaltungen für health institutions in rural Africa, the einheimische Studenten und Ärzte. introduction of diagnostic ultrasound in Daneben sind mehrere Projekte entstan- internal medicine and obstetrics for African den, die neue Erkenntnisse und Techni- district hospitals, to courses for de- ken in tropischen Ländern einsetzen und velopment aid workers to confront them mit wissenschaftlichen Methoden untersu- with the medical realities of their host chen. Diese angewandte Forschung countries, an internet-based, interactive (implementation research) hat sich vor al- training module on HIV/AIDS and work- lem auf die beiden großen tropischen In- shops on the management of highly fektionskrankheiten Malaria und Schlaf- contagious diseases. In the past ten years, krankheit fokalisiert. Schwerpunkt sind more than 3,000 health professionals dabei Untersuchungen zum Einsatz in- could benefit from those training units. This sektizidimprägnierter Moskitonetze zur figure still excludes medical students and Malariakontrolle in mehreren afrikanischen doctors who participated in regular lecture Ländern, Studien zu Verlauf und Epidemi- series, courses and seminars offered by ologie der Schlafkrankheit in Angola sowie our institution. in-vitro-Untersuchungen neuer Wirkstoffe gegen Trypanosomen. In addition, projects have been imple- mented to develop and test new approaches and tools in tropical countries with scientific methods. This „implementation research“ is focusing on the two 3.13 The Department of Tro- big tropical infectious diseases malaria pical Medicine of the Medical and human African trypanosomiasis Mission Hospital (sleeping sickness). Current research priorities are studies on the use of Tropical medicine is playing an increasing insecticide-impregnated bed nets for role globally, but also in Germany. Health malaria control in various African countries, services dealing with tropical infections are on the clinical presentation and the often overstretched. This might lead to epidemiology of sleeping sickness in An- insufficient care for the patients. Classical gola and on cytotoxicity of various new medical research aims at acquiring new compounds against trypanosomes using knowledge in basic sciences, at under- in vitro screening assays. standing the pathophysiology of diseases or at developing theoretical approaches for new drugs and treatment concepts. Another possibility to react to the chal- lenges in tropical medicine, however, is the attempt to offer training to medical, nursing and laboratory personnel on how to improve the care of their patients and how to make the best use of existing re- sources. This is exactly the field in which the Tropi- cal Department of the Medical Mission Hos- pital in close cooperation with the units of the Medical Mission Institute is engaged. In the past ten years, numerous training units on various topics and for different target groups have been organised. Their spectrum ranges from courses in the use of appropriate laboratory techniques for

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3.14 Publications of the Institutions of the Research Center for Infectious Diseases: 2005/2006

3-1 Chair of Virology

Abt, M., Müller, N., and Schneider-Schaulies, S. (2006) DC in measles pathogenesis. John Wiley & Son’s Dendritic cells. 855- 868. Avota, E., Harms, H., and Schneider-Schaulies, S. (2006) Measles virus induces expression of SIP110, a constitutively membrane clustered lipid phosphatase, which inhibits T cell proliferation. Cell Microbiol 8: 1826-1839. Beddows, S., Franti, M., Dey, A.K., Kirschner, M., Iyer, S.P., Fisch, D.C., Ketas, T., Klasse, P.J., Maddon, P.J., Olson, W.C and Moore, J.P. (2007) A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120. Virology 360: 329- 40. Beddows, S., Kirschner, M., Campbell-Gardener, L., Franti, M., Dey, AK., Iyer, S.P., Maddon, P.J., Paluch, M., Master, A., Overbaugh, J., VanCott, T., Olson, W.C., Moore, J.P. (2006) Construction and characterization of soluble, cleaved, and stabilized trimeric Env proteins based on HIV type 1 Env subtype A. AIDS Res Hum Retroviruses 22: 569-79. Beddows, S., Schulke, N., Kirschner, M., Barnes, K., Franti, M., Michael, E., Ketas, T., Sanders, R.W., Maddon, P.J., Olson, W.C., and Moore, J.P. (2005) Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol 79: 8812-27. Bender, F.L.P., Fischer, M., Funk, N., Orel, N., Rethwilm, A., and Sendtner, M. (2007) High-efficiency gene transfer into cultured embryonic motoneurons using recombinant lentiviruses. Histochem Cell Biol 127: 439-48. Bodem, J., Kräusslich, H.G., and Rethwilm, A. (2007) Acetylation of the foamy virus transactivator Tas by PCAF augments promoter-binding affinity and viral transcription. J Gen Virol 88: 259-63. Cartellieri, M., Rudolph, W., Herchenröder, O., Lindemann, D., and Rethwilm, A. (2005) Determination of the relative amounts of gag and pol proteins in foamy virus particles. Retrovirology 2: 44. Cartellieri, M., Herchenröder, O., Rudolph, W., Heinkelein, M., Lindemann, D., Zentgraf, H., and Rethwilm, A. (2005) N-terminal gag domain required for foamy virus particle assembly and export. J Virol 79: 12464-12476. Cigler, P. ,Kozisek, M., Rrezácová, P., Brynda, J., Otwinovski, Z., Pokorná, J., Plesek, J., Grüner, B., Dolecková, L., Masa, M., Sedládek, J., Bodem, J., Kräusslich, H.G., Král, V. and Konvalinka, J. (2005) From non-peptide towards non-carbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. PNAS 102: 15394-9. De Witte, L., Abt, M., Schneider-Schaulies, S., Van Kooyk, Y., and Geijtenbeek, T.B.H. (2006) Measles virus targets DC-SIGN to enhance dendritic cell infection. J Virol 80: 3477-3486. Doerries, K. (2006) Human polyomavirus JC and BK persistent infection. Adv Exp Med Biol 577: 102-16. Gronen, F., Ruprecht, K., Weissbrich, B., Klinker, E., Kroner, A., Hofstetter, H.H., and Rieckmann, P. (2006) Frequency analysis of HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol 185-92. Grünblatt, E., Koutsilieri, E., Hoyer, S., and Riederer, P. (2006) Gene expression alterations in brain areas of intracerebroventricular streptozotocin-treated rat. J Alzheimer´s disease 9: 261-271. Grünblatt, E., Schlosser, R., Fischer, P., Fischer, M.O., Li, J., Koutsilieri, E., Wichart, I., Sterba, N., Rujescu, D., Moller, H.J., Adamcyk, W., Dittrich, B., Muller, F., Oberegger, K., Gatterer, G., Jellinger, K.J., Mostafaie, N., Jungwirth, S., Huber, K., Tragl, K.H., Danielczyk, W., and Riederer, P. (2005) Oxidative stress related markers in the „VITA“ and the centenarian projects. Neurobiol Aging 26: 429-438. Heinkelein, M., Hoffmann, U., Lücke, M., Imrich, H., Müller, J.G., Meixensberger, J., Westphal, M., Kretschmer, A., and Rethwilm, A. (2005) Experimental therapy of allogeneic solid tumours induced in athymic mice with suicide gene-transducing replication- competent foamy virus vectors. Cancer Gene Ther 12: 947-953. Inhoff, O., Doerries, K., Doerries, R., Scharf, J., Groden, C., Schadendorf, G., and Schadendorf, D. (2006) Disseminated Cutaneous Kaposi Sarcoma and Progressive Multifocal Leukencephalopathy in a Patient with Idiopathic CD4+ T-Lymphocytopenia. Archives of Dermatology (in press). Jackson, G.S., McKintosh, E., Flechsig, E., Prodromidou, K., Hirsch, P., Linehan, J., Brandner, S., Clarke, A.R., Weissmann, C., and Collinge, J. (2005) An enzyme-detergent method for effective prion decontamination of surgical steel. J Gen Virol 86: 869-78. Kirschner, M., Montazem, A., Hilaire, H.S., and Radu, A. (2006) Long-term culture of human gingival keratinocyte progenitor cells by down-regulation of 14-3-3 sigma. Stem Cells Dev 15: 556-65. Kirschner, M., Monrose, V., Paluch, M., Techodamrongsin, N., Rethwilm, A., and Moore J.P. (2006) The production of cleaved, trimeric human immunodeficiency virus type 1, (HIV-1) envelope glycoprotein vaccine antigens and infectious pseudoviruses using linear polyethylenimine as a transfection reagent. Protein Expr Purif 48: 61-8.

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Koutsilieri, E., Arendt, G., Neuen-Jacob, E., Scheller, C., Grünblatt, E., and Riederer, P. (2006) HIV dementia: a neurode- generative disorder with viral etiology. Handbook of Neurochemistry and Molecular Neurobiology, 3rd ed. (in press). Kraus, M.R., Schafer, A., Bentink, T., Scheurlen, M., Weissbrich, B., Al-Taie, O., and Seufert, J. (2005) Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression? J Endocrinol 185: 345-352. Lehmann, C., Duprex, P., Krohne, G., Rima, B.K., and Schneider-Schaulies, S. (2007). Measles virus M and F proteins associate with detergent resistant membrane fractions and independently promote formation of virus-like particles. J. Gen. Virol. 88: 243-50. Lehmann, C., Shishkova, Y., and Schneider-Schaulies, S. (2007). Viruses and dendritic cells: enemy mine. Cell Microbiol 9: 279-89. Li, J., Scheller, C., Koutsilieri, E., Griffiths, F., Beart, P.M., Mercer, L.D., Halliday, G., Kettle, E., Rowe, D., Riederer, P., Gerlach, M., Rodriguez, M., and Double, K.L. Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells (2005). J Neurochem 95: 599-608. Lüftenegger, D., Picard-Maureau, M., Stanke, N., Rethwilm, A., and Lindemann, D. (2005) Analysis and function of prototype foamy virus envelope N-glycosylation. J Virol 79: 7664-7672. Maschmann, J., Hamprecht, K., Weissbrich, B., Dietz, K., Jahn, G., and Speer, C.P. (2006) Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal 91: F288-290. Mössner, R., Yun, S.W., Lesch, K.P., Gerlach, M., Klein, M.A., and Riederer, P. (2006) Unaltered susceptibility to scrapie in serotonin transporter deficient mice. Neurochem Int 49: 454-8. Müller, N., Avota, E., Schneider-Schaulies, J., Krohne, G., and Schneider-Schaulies, S. (2006) Measles virus contact impedes cytoskeletal remodeling required for T cell adhesion and immunological synapse formation. Traffic 7: 1-10. Müller, N., Avota, E., Schneider-Schaulies, J., Harms, H., Krohne, G., and Schneider-Schaulies, S. (2006) Measles virus contact impedes cytoskeletal remodeling associated with T cell adhesion, spreading and CD3 clustering in the immunological synapse. Traffic 7: 1-10. Nowrouzi, A., Dietrich, M., Klanke, C., Heinkelein, M., Rammling M., Dandekar, T., Kalle, C., and Rethwilm, A. (2006) Genome- wide mapping of foamy virus integrations in a human cell line. J Gen Virol 87: 1339-1347. Obojes, K., Andres, O., Kim, K.S., Däubener, W., and Schneider-Schaulies, J. (2005) Indolamine 2,3-dioxygenase (IDO) mediates cell type specific anti-measles virus activity of gamma interferon. J Virol 79: 7768-7776. Peters, K., Wiktorowicz, T., Heinkelein, M., and Rethwilm, A. (2005) RNA and protein requirements for the incorporation of pol protein into foamy virus particles. J Virol 79: 7005-7013. Rethwilm., A (2005): Foamy Viruses. Topley & Wilson’s Microbiology, 10th ed., 1304-1321. Reuter, T., Weissbrich, B., Schneider-Schaulies, S., and Schneider-Schaulies, J. (2006). RNA interference with measles virus polymerase mRNA efficiently prevents, and with matrix protein mRNA enhances viral transcription. J Virol 80: 5951-5957. Rohayem., J., Dumke, R., Jäger, K., Schröter-Bobsin, U., Mogel, M., Kruse, A., Jacobs, E., and Rethwilm, A. (2006) Viral load in the river Elbe during the flood in August 2000. Intervirology 49: 370-376. Rohayem, J., Münch, J. and Rethwilm, A. (2005) Recombination in the norovirus capsid gene. J Virol 79: 4977-4990. Rueger, M.A., Miletic, H., Dörries, K., Wyen, C., Deckert, M., Fätkenheuer, G., Jacobs, A.H. (2006) Long-term remission in progressive multifocal leukoencephalopathy caused by idiopathic CD4+ T-lymphocytopenia: a case report. Clinical Infectious Diseases 42: 53-56. Ruprecht, K., Obojes, K., Wengel, V., Gronen, F., Perron, H., Schneider-Schaulies, J., and Rieckmann, P. (2006) Regulation of human endogenous retrovirus W protein expression by herpes simplex virus type 1: Implications for multiple sclerosis. J Neurovirol 12: 65-71. Santibanez, S., Niewiesk, S., Heider, A., Schneider-Schaulies, J., Berbers, G.A.M., Zimmermann, A., Halenius, A., Wolbert, A., Deitemeier, I., Tischer, A., and Hengel, H. (2005) Probing neutralzing antibody responses against emerging measles viruses (MV): immune selection of MV by H protein-specific antibodies? J Gen Virol 86: 365-374. Scheller, C., Knoferle, J., Ullrich, A., Prottengeier, J., Racek, T., Sopper, S., Jassoy, C., Rethwilm, A., and Koutsilieri, E. (2006) Caspase inhibition in apoptotic T cells triggers necrotic cell death depending on the cell type and the proapoptotic stimulus. J Cell Biochem 97:1350-1361. Scheller, C., Riederer, P., Gerlach, M., and Koutsilieri E. (2006). Induction of proinflammatory signaling due to inhibition of apoptosis in T cells-implications for the CNS. J Neural Transm 71: 45-51. Scheller, C., Ullrich, A., Lamla, S., Dittmer, U., Rethwilm, A., and Koutsilieri, E. (2006) Dual activity of phosphorothioate CpG- oligodeoxynucleotides on HIV: Reactivation of latent provirus and inhibition of productive infection in human T cells. Ann N Y Acad Sci 1091: 540-7. Scheller, C., Sopper, S., Jenuwein, M., Neuen-Jacob, E., Tatschner, T., Grünblatt, E., ter Meulen, V., Riederer, P., and Koutsilieri, E. (2005) Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. J Neurochem 95: 377-387.

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Schneider-Schaulies, J., Schneider-Schaulies, S., and ter Meulen, V. (2005) Infections of the Central Nervous System. Topley & Wilson’s Virology. 10th ed., 1403-1442. Schneider-Schaulies, S., and Dittmer, U. (2006). Silencing T cells or T cell silencing: concepts in virus-induced immunosuppression. J Gen Virol 87: 1423-38. Schneider-Schaulies, S., and Bellini, W.J (2005) Morbilliviruses: Measles virus. Topley & Wilson’s Virology, 10th ed., 712-742. Schmidt, E., Weissbrich, B., Brocker, E.B., Fleischer, K., Goebeler, M., and Stich, A. (2006) Orf followed by erythema multiforme. J Eur Acad Dermatol Venereol 20: 612-613. Singethan, K., Topfstedt, E., Schubert, S., Duprex, W.P., Rima, B.K., and Schneider-Schaulies, J. (2006) CD9-dependent regulation of canine distemper virus (CDV)-induced cell-cell fusion segregates with extracellular domain of the haemagglutinin. J Gen Virol 87: 1635-1642. Schubert, S., Moeller, K., Wiese, S., Duprex, P.W., Rima, B.K., Niewiesk, S., and Schneider-Schaulies, J. (2006) A mouse model of persistent brain infection with recombinant measles virus. J Gen Virol 87: 2011-2019. Stange, A., Manigel, I., Peters, K., Heinkelein, M., Stange, N., Rethwilm, A., Zentgraf, H., and Lindemann, D., (2005) Characterization of prototypic foamy virus late assembly domain motifs and their role in particle egress and infectivity. J Virol 79: 5466-5476. Sticht, J., Humbert, M., Findlow, S., Bodem, J., Müller, B., Dietrich, U., Werner, J., and Kräusslich, H.G. (2005) A peptide inhibitor of HIV-1 assembly in vitro. Nat Struct Biol 12: 671-7. Weissbrich, B., Neske, F., Schubert, J., Tollmann, F., Blath, K., Blessing, K., and Kreth, H.W. (2006) Frequent detection of bocavirus DNA in German children with respiratory tract infections. BMC Infect Dis 6: 109. Winzer, R., Langmann, P., Zilly, M., Tollmann, F., Schubert. J., Klinker, H., and Weissbrich, B. (2005) No influence of the P- glycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naive HIV-positive patients. Ann Clin Microbiol Antimicrob 4: 3. Yun, S.W., Gerlach, M., Riederer, P., and Klein M.A. (2006) Oxidative stress in the brain at early preclinical stages of mouse scrapie. Exp Neurol 201: 90-8.

3-2 Chair of Immunology:

Beaudette-Zlatanova BC, Whalen B, Zipris D, Yagita H, Rozing J, Groen H, Benjamin CD, Hunig T, Drexhage HA, Ansari MJ, Leif J, Mordes JP, Greiner DL, Sayegh MH, Rossini AA. (2006) Costimulation and autoimmune diabetes in BB rats. Am J Transplant. May;6(5 Pt 1):894-902. Berberich-Siebelt, F., Berberich, I., Andrulis, M., Santner-Nanan, B., Jha, M. K., Klein-Hessling, S., Schimpl, A., and Serfling, E. (2006) SUMOylation interferes with CCAAT/enhancer-binding protein beta-mediated c-myc repression, but not IL-4 activation in T cells. J Immunol 176: 4843-4851 Berger, S., Wolfer, D.P., Selbach, O., Alter, H., Erdmann, G., Reichardt, H.M., Chepkova, A.N., Welzl, H., Haas, H.L., Lipp, H.P., and Schütz, G. (2006) Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity. Proc Natl Acad Sci USA 103: 195-200. Beyersdorf, N., Gaupp, S., Balbach, K., Schmidt, J., Toyka, K.V., Lin, C.H., Hanke, T., Hunig, T., Kerkau, T., and Gold, R. (2005a) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202: 445-455. Beyersdorf, N., Hanke, T., Kerkau, T., and Hünig, T. (2005). Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Annals of the Rheumatic Diseases 64;91-95. Beyersdorf, N., Hanke, T., Kerkau, T., and Hünig, T. (2006). CD28 superagonists put a break on autoimmunity by preferentially activating CD4+CD25+ regulatory T cells. Autoimmunity Reviews 5:40-45. Beyersdorf N, Balbach K, Hunig T, Kerkau T. (2006) Large-scale expansion of rat CD4 CD25 T cells in the absence of T-cell receoptor stimulation. Immunology Cao, Yi, Catherine Toben, Shin-Yooung Na, Kirsten Stark, Lars Nitschke, Alan Peterson, Ralf Gold, Anneliese Schimpl and Thomas Hünig (2006). Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes. Eur. J. Immunol. 36:207-215. Dennehy KM, Elias F, Zeder-Lutz G, Ding X, Altschuh D, Luhder F, Hunig T. (2006) Cutting edge: monovalency of CD28 maintains the antigen dependence of T cell costimulatory responses. J Immunol. May 15;176(10):5725-9. Dennehy KM, Elias F, Na S-Y, Fischer K-D, Hünig T, Lühder F. Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome. The Journal of Immunology, in press. Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, Fennelly JA, Vowles C, Hanke T, Walse B, Hunig T, Sorensen P, Stuart DI, Davis SJ. (2005) Crystal structure of a soluble CD28-Fab complex. Nat Immunol. Mar;6(3):271-9. Herrmann, M.M., Gaertner, S., Stadelmann, C., van den Brandt, J., Boscke, R., Budach, W., Reichardt, H.M., and Weissert, R. (2005) Tolerance induction by bone marrow transplantation in a multiple sclerosis model. Blood 106: 1875-1883.

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Herold, M.J., McPherson, K.G., and Reichardt, H.M. (2006) Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 63: 60-72. Herold, M. J., Zeitz, J., Pelzer, C., Kraus, C., Peters, A., Wohlleben, G., and Berberich, I. (2006) The stability and anti-apoptotic function of A1 are controlled by its C terminus. J Biol Chem 281: 13663-13671 Hünig, T. and Dennehy, K. (2005). CD28 superagonists: Mode of action and therapeutic potential. Immunology Letters 100 (2005) 21-28. Kerstan, A. and Hünig, T. (2005). Cyclosporin A abolishes CD28-mediated resistance to apoptosis via superinduction of caspase-3. in revision. Kerstan A, Armbruster N, Leverkus M, Hünig T, (2006) Cyclosporin A abolishes CD28-mediated resistance to CD95-induced apoptosis via superinduction of caspase-3. J. Immunol. 177: 7689-7697 Na, Shin-Young, Yi Cao, Catherine Toben, Kevin Dennehy, Lars Nitschke, Christine Stadelmann, Ralf Gold, Anneliese Schimpl, Thomas Hünig (2006). Regulatory T-cells prevent spontaneous CD8 T-cell-mediated autoimmune encephalomyelitis. Submitted. Pyz, E., Naidenko, O., Miyake, S., Yamamura, T., Berberich, I., Cardell, S., Kronenberg, M., and Herrmann, T. (2006) The complementarity determining region 2 of BV8S2 (V beta 8.2) contributes to antigen recognition by rat invariant NKT cell TCR. J Immunol 176: 7447-7455 Reichardt, H.M., Gold, R., and Lühder, F. (2006) Glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis. Expert Rev Neurotherapeutics 6: in press. Rincon-Orozco, B., Kunzmann, V., Wrobel, P., Kabelitz, D., Steinle, A., Herrmann, T. (2005) Activation of V gamma 9V delta 2 T cells by NKG2D.J Immunol. 175: 2144-51. Rodríguez-Palmero, M., À. Franch, M. Castell, C. Pelegrí, F.J. Pérez-Cano, C. Kleinschnitz, G. Stoll, T. Hünig, and C. Castellote (2006). Effective Treatment of Adjuvant Arthritis with a stimulatory CD28-specific monoclonal antibody. The Journal of Rheumatology 2006; 33(1):110-8 Tischner D, Weishaupt A, van den Brandt J, Müller N, Beyersdorf N, Ip CW, Toyka KV, Hünig T, Gold R, Kerkau T, Reichardt HM (2006) Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of Multiple Sclerosis. Brain 129:2635-2647. Tuckermann, J.P., Kleiman, A., McPherson, K.G., and Reichardt, H.M. (2005) Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci 42: 71-104. van den Brandt, J., Kwon, S.H., Hünig, T., McPherson, K.G., and Reichardt, H.M. (2005). Sustained preTCR expression in Notch1IC transgenic rats impairs T cell maturation and selection. Journal of Immunology 174: 7845-7852. van den Brandt, J., Kwon, S.H., McPherson, K.G., Petrovic, S., Zettl, A., Müller-Hermelink, H.K., and Reichardt, H.M. (2006) Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats. Eur J Immunol 36: 2223-2234. Verschelde, C., Michonneau, D., Trescol-Biemont, M. C., Berberich, I., Schimpl, A., and Bonnefoy-Berard, N. (2006) Overexpression of the antiapoptotic protein A1 promotes the survival of double positive thymocytes awaiting positive selection. Cell Death Differ 13: 1213-1221 Voigt, H., Schrama, D., Eggert, A.O., Vetter, C.S., Müller-Blech, K., Reichardt, H.M., Andersen, M.H., Becker, J.C., and Lühder, F. (2006) CD28-mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol 143: 93-102. Wang, D., Müller, N., McPherson, K.G., and Reichardt, H.M. (2006) Glucocorticoids engage different signal transduction pathways to induce apoptosis in thymocytes and mature T cells. J Immunol 176: 1695-1702.

3-3 Institute of Hygiene and Microbiology:

Abele-Horn, M., Vogel, U., Klare, I., Konstabel, C., Trabold, R., Kurihara, R., Witte, W., Kreth, W., Schlegel, P.G., and Claus, H. Molecular epidemiology of hospital-acquired vancomycin-resistant enterococci. J Clin Microbiol in press Abele-Horn, M., Stoy, K., Frosch, M. and reinert, R.R. (2006) Comparative evaluation of a new Vitek 2 system for identification and antimicrobial susceptibility testing of Streptococcus pneumoniae. Eur. J. Clin. Microbiol. Infect. Dis. 25: 55-57. Abele-Horn, M., Hommers, L., Trabold, R. and frosch, M. (2006) Validation of VITEK 2 version 4.01 software for detection, identification, and classification of glycopeptide-resistant enterococci. J. Clin. Microbiol. 44: 71-76. Aires-de-Sousa, M., 18 other authors, Vogel, U., Westh, H., Xu, J. and Witte, W. (2006). High Inter-laboratory Reproducibility of DNA Sequence-Based Typing of Bacteria in a Multicenter Study. J Clin Microbiol 44: 619-621. Berg, T., Schild, S., and Reidl, J. (2006) Characterisation of the regulation of the chitosan-phospho-transferase system in Vibrio cholerae. Microbiol, in press. Brehm, K., Spiliotis, M., Zavala-Gongora, R., Konrad, C., and Frosch, M. (2006) The molecular mechanisms of larval cestode development: first steps into an unknown world. Parasitol Int 55: S15-S21.

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Claus, H., Harmsen, D., and Vogel, U. (2005). DNA-sequence based tandem repeat analysis of the clfB gene is less discriminatory than spa-typing for methicillin-resistant Staphylococcus aureus. Intern J Med Microbiol 294:525-528. Claus, H., Maiden, M.C.J., Wilson, D.J., McCarthy, N.D., Jolley, K.A., Urwin, R., Hessler, F., Frosch, M. and Vogel, U. (2005). Genetic analysis of meningococci carried by children and young adults. J Infect Dis 191:1263-1271. Claus, H., Vogel, U., Swiderek, S., Frosch, M., and Schoen, S. 2006. Microarray analyses of meningococcal genome composition and gene regulation: review of the recent literature. In revision FEMS Microbiol. Rev., in press. Elias, J. and Vogel, U. IS1301 fingerprint analysis of Neisseria meningitidis strains belonging to the ET-15 clone. J Clin Microbiol, in press. Elias, J., Frosch, M., and Vogel, U. 2006. Meningokokkeninfektionen in Deutschland 2005: Daten des Nationalen Referenz- zentrums. ImpfDialog 3:119-124. Elias, J., Harmsen, D., Claus, H., Hellenbrand, W., Frosch, M., and Vogel, U. 2006. Spatio-temporal analysis of meningococcal disease in Germany. Emerg Infect Dis 12:1689-1695. Elias, J., Health Office in the Rural District Office Wartburgkreis, Claus, H., Frosch, M., and Vogel, U. Evidence for indirect nosocomial transmission of Neisseria meningitidis resulting in two cases of invasive meningococcal disease. J Clin Microbiol in press Findlow, H., Vogel, U., Mueller, J.E., Curry, A., Njanpop-Lafourcade, B.M., Claus, H., Gray, S.J., Yaro, S., Traoré, Y., Sangaré, L., Nicolas, P., Gessner, B.D., and Borrow, R. Three cases of invasive meningococcal disease in Burkina Faso caused by a capsule null locus strain circulating among healthy carriers. J. Infect. Dis., in press. Fox, A.J., Taha, M.K., and Vogel, U. Standardized non-culture techniques recommended for European reference laboratories. FEMS Microbiol. Rev., in press. Frosch, M. and Maiden, M. The European networking for combating meningococcal disease. FEMS Microbiol. Rev., in press. Frosch, M. and Vogel, U. (2006) Structure and genetics of the meningococcal capsule. In: Handbook of Meningococcal Disease. Ed.: Frosch, M. Maiden, M.C.J. 1st. edition. Wiley-VCH, Weinheim. Geiger, D., Debus, E.S., Ziegler, U.E., Larena-Avellaneda, A., Frosch, M., Thiede, A. and Dietz, U.A. (2005) Capillary activity of surgical sutures and suture-dependent bacterial transport: a qualitative study. Surg. Infect. 6: 377-383. Gelmedin, V., Zavala-Gongora, R., Fernandez, C., and Brehm, K. (2005) Echinococcus multilocularis: cloning and characterization of a member of the SNW/SKIP family of transcriptional coregulators. Exp Parasitol 111: 115-120. Gerlach, G., and Reidl, J. (2006) NAD-Pathway in Pasteurellaceae: Simplification of a complex pathway. J Bacteriol 188:6719- 6727. Hautmann, W., Harms, I., Vogel, U., Zirngibl, A., and Wildner, M. (2005). Cluster von Meningokokkenerkrankungen im Allgäu – Interventionsstrategien. Gesundheitswesen. 67: 853-857. Heldwein, K., Biedermann, H.G., Hamperl, W.D., Bretzel, G., Loscher, T., Laregina, D., Frosch, M., Buttner, D.W. and Tappe, D. (2006) Subcutaneous Taenia crassiceps infection in a patient with non-Hodgkin’s lymphoma. Am. J. Trop. Med. Hyg. 75: 108-111. Jarva, H, Ram, S., Vogel, U., Blom, A.M. and Meri, S. (2005) Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. J Immunol 174(10):6299-6307. Jung, S., Zimmer, S., Lueneberg, E., Frosch, M., Karch, H., Korn, T. and Toyka, K.V. (2005) Lipooligosaccharide of campylobacter jejuni prevents myelin-specific enteral tolerance to autoimmune neuritis – a potential mechanism in Guillain-Barre syndrome. Neurosci. Lett. 381: 175-178. Khayath, N., Vicogne, J., Ahier, A., Ben Younes, A., Konrad, C., Trolet, J., Viscogliosi, E., Brehm, K. and Dissous, C. (2006) Diversification of the insulin receptor family in the helminth parasite Schistosoma mansoni. FEBS J., in press. Kurzai O., Schmitt, C., Claus, H., Vogel, U., Frosch, M, Kolb-Maurer, A. (2005) Carbohydrate composition of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol 7:1319- 34. Kurzai, O., Frosch, M. (2006) Cellular immune responses in meningococcal disease. In: Frosch, M., Maiden, M. (eds.) Handbook of Meningococcal Disease, Wiley-VCH, Weinheim, Germany. Kurzai, O., Schmitt, C., Bröcker, E., Frosch, M., Kolb-Mäurer, A. (2006) Polymorphism of Candida albicans is a major factor in the interaction with human dendritic cells. Int J Med Microbiol 295:121-127. Kurzai, O., Schmitt, C., Claus, H., Vogel, U., Frosch, M., Kolb-Mäurer, A. (2005) Carbohydrate composition of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol 7:1319- 1334. Lappann, M., Haagensen, J.A.J., Claus, H., Vogel, U., and Molin, S. Meningococcal biofilm formation: Structure, development, and phenotypes in a standardized continuous flow system. Mol Microbiol in press. Madico, G., Welsch, J.A., Lewis, L.A., McNaughton, A., Perlman, D.H., Costello, C.E., Ngampasutadol, J., Vogel, U., Granoff, D.M., Ram, S. (2006) The Meningococcal Vaccine Candidate GNA1870 Binds the Complement Regulatory Protein Factor H and Enhances Serum Resistance. J Immunol 177:501-10.

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Merdanovic, M., Sauer, S., and Reidl, J. (2005) Coupling of NAD+ biosynthesis and nicotinamide ribosyl transport: Characterization of NadR ribonucleotide-kinase mutants of Haemohilus influenzae. J Bacteriol 187:4410-4420. Müller, I., Brade, V., Hagedorn, H.J., Straube, E., Schörner, C., Frosch, M., Hlobil, H., Stanek, G. and Hunfeld, K.P. (2006) Is serological testing a reliable tool in laboratory diagnosis of syphilis? Meta-analysis of eight external quality control surveys performed by the german infection serology proficiency testing program. J. Clin. Microbiol. 44: 1335-1341. Nikulin, J., Panzner, U., Frosch, M. and Schubert-Unkmeir, A. (2006) Intracellular survival and replication of Neisseria meningitidis in human brain microvascular endothelial cells. Int J Med Microbiol. 296: 553-558. Oppermann, H., Thriene, B., Irmscher, H.M., Gräfe, L., Borrmann, M., Bellstedt, D., Kaynak, S., Hellenbrand, W., und Vogel, U. Meningokokken-Trägerstatus von Gymnasiasten und mögliche Risikofaktoren. Gesundheitswesen. in press. Ram, S. and Vogel, U. (2006) Role of Complement in Defense Against Meningococcal Infection. In: Handbook of Meningococcal Disease. Ed.: Frosch, M. Maiden, M.C.J. 1st. edition. Wiley-VCH, Weinheim. Schild, S., Lamprecht, A.-K., and Reidl, J. (2005) Functional characterization of surface polymer:lipid A-core ligases of Vibrio cholerae. J Biol Chem 280: 25936-25947. Schild, S., Lamprecht, A.-K., Fourestier, C., Lauriano C.M., Klose, K.E., and Reidl, J. (2005) Characterizing LPS and core lipid A mutant O1 and O139 Vibrio cholerae strains for adherence properties on mucus producing cell line HT-29-Rev MTX and virulence in mice. Int J Med Microbiol 295:243-251. Schoen, C., Claus, H., Vogel, U., and Frosch, M. (2006) The genomes of pathogenic Neissera species. In: Pathogenomics, edited by J. Hacker and U. Dobrindt, Weinheim:Wiley-VCH, 2006, p. 231-255. Schoen C. and H. Claus (2006) Neisseria meningitidis genome sequencing projects. In: Frosch M, Maiden MC, eds. Meningococcal Disease: Pathogenicity and Prevention. Weinheim: Wiley-VCH; pp. 77-97. Schrauder, A., Claus, H., Elias, J., Vogel, U., Haas, W., and Hellenbrand, W. Capture-Recapture Analysis to estimate the Incidence of Invasive Meningococcal Disease in Germany, 2003. Epidemiol Infect in press Schröter, M., Elias, J., Hellenbrand, W., Ziemer, B., Baumeister, H., and Vogel, U. 2006. Die Epidemiologie von Neisseria meningitidis in NRW. Rheinisches Ärzteblatt 4: 19-21. Schubert-Unkmeir A., A. Schramm-Glück, M. Frosch and C. Schoen. Transcriptome analyses in the interaction of Neisseria meningitidis with mammalian host cells. Methods Mol Biol in press. Schubert-Unkmeir, A., Sokolova, O., Panzner, U., Egenthaler, M. and Frosch, M. Gene expression pattern in human brain endothelial cells in response to Neisseria meningitidis. Infect. Immun., in press. Siauw, C., Kobsar, A., Dornieden C, Beyrich C, Schinke B, Schubert-Unkmeir, A., Abele-Horn, M., Speer, C., Eigenthaler, M. (2006) Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signalling cascades. Thromb Haemost. 95: 836-849. Spiliotis, M., Konrad, C., Gelmedin, V., Tappe, D., Brückner, S., Mösch, H.U., and Brehm, K. (2006) Characterisation of EmMPK1, an ERK-like MAP kinase from Echinococcus multilocularis which is activated in response to human epidermal growth factor. Int J Parasitol 36: 1097-1112. Spiliotis, M., Tappe, D., Brückner, S., Mösch, H.U., and Brehm, K. (2005) Molecular cloning and characterization of Ras- and Raf-homologues from the fox-tapeworm Echinococcus multilocularis. Mol Biochem Parasitol 193: 225-237. Stummeyer, K., Schwarzer, D., Claus, H., Vogel, U., Gerardy-Schahn, R., and Mühlenhoff, M. 2006. Evolution of bacteriophages infecting encapsulated bacteria: lessons from Escherichia coli K1-specific phages. Mol Microbiol 60:1123-35. Swiderek, H., Claus, H., Frosch, M., and Vogel, U. (2005). Evaluation of custom-made DNA microarrays for multilocus sequence typing of Neisseria meningitidis. Intern J Med Microbiol 295:39-45. Taha, M.-K., Alonso, J.-M., Clarke, S.C., Caugant, D.A., Diggle, M.A., Fox, A., Frosch, M., Gray, S.J., Guiver, M., Heuberger, S., Cafferkey, M., Kalmusova, J., Klem, A., Kriz, P., Kesanopoulos, K., Marsh, J., Mölling, P., Murphy, K., Olcén, P., Sanou, O., Tzanakaki, G., and Vogel, U. (2005) Interlaboratory comparison of PCR-based identification and genogrouping of Neisseria meningitidis. J Clin Microbiol 43:144-149. Tappe, D., Winzer, R., Büttner, D.W., Strobel, P., Stich, A., Klinker, H. and Frosch, M. (2006) Linguatuliasis in Germany. Emerg. Inf. Dis. 12: 1034-1036. Tappe, D., Dirks, J., Müller, R., Brederlau, J., Abele-Horn, M., Suerbaum, S., Kurzai, O. (2005) Fatal Clostridium tertium septicemia in a nonneutropenic patient. J Infect 50:76-80. Tappe, D., Claus, H., Kern, J., Marzinzig, A., Frosch, M. and Abele-Horn, M. (2006) First case of febrile bacteremia due to a wild- type and small-colony variant of Escherichia coli. Eur. J. Clin. Microbiol. Infect. Dis. 25: 31-34. Trotter, C.L., Chandra, M., Cano, R., Larrauri, A., Ramsay, M.E., Brehony, C., Jolley, K.A., Maiden, M.C., Heuberger, S. and Frosch, M. A surveillance network for meningococcal disease in Europe. FEMS Microbiol. Rev., in press. Valenza, G., Burgemeister, S., Girschick, H., Schoen, C., Veihelmann, S., Moter, A., Haban, V., Vogel, U., and Schlagenhauf, U. 2006. Analysis of the periodontal microbiota in childhood-type hypophosphatasia. Int J Med Microbiol 296:493-500. Valenza, G., Kallmann, B., Berend, A., Mlynski, R., Nöckler, K., Kurzai, O., Frosch, M., Abele-Horn, M. (2006) Isolation of Brucella melitensis from a patient with hearing loss. Eur J Clin Microbiol Infect Dis 25:67-68.

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Valenza, G., Valenza, R., Brederlau, J., Frosch, M., Kurzai, O. (2006) Identification of Candida fabianii as a cause of lethal septicaemia. Mycoses 49:331-334. Vehreschild, J.J., Krüger, K., Kurzai, O., Wickenhauser, C., Behringer, K., Tox, U., Cornely, O.A. (2006) Salvage therapy of refractory chronic disseminated candidiasis in a patient with acute myeloid leukaemia and secondary prophylaxis during allogeneic stem cell transplantation. Mycoses 49:42-47. Vogel, U., Elias, J., and Frosch, M. (2005). Epidemiologie der Meningokokkeninfektion aus Sicht des Nationalen Referenz- zentrums für Meningokokken. Impfdialog 3:117-121. Vogel, U., Kurzai, O., Claus, H., Knaust, A., and Pitten, F.-A.. (2005) Spa-Typisierung von Methicillin-resistenten Staphylococcus aureus Stämmen am Universitätsklinikum Würzburg. Der Mikrobiologe. 15:131-135. Weber, M.V.R., Claus, H., Maiden, M.C.J., Frosch, M., and Vogel, U. (2006) Genetic mechanisms for loss of encapsulation in polysialyltransferase-gene-positive meningococci isolated from healthy carriers. Int J Med Microbiol 296:475-84. Zavala-Gongora, R., Kroner, A., Bernthaler, P., Knaus, P., and Brehm, K. (2006) A member of the transforming growth factor-b receptor family of Echinococcus multilocularis is activated by human bone morphogenetic protein 2. Mol Biochem Parasitol 146: 265-271.

3-4 Chair of Microbiology:

Armstrong, S.K., and Gross, R. (2006) Metabolism and physiology of Bordetella species. In: Molecular Biology of Bordetella. Ed.: Locht, C. Horizon Scientific Press, Norfolk, U.K., in press. Beier, D., and Gross, R. (2006) Regulation of bacterial virulence by two-component systems. Curr Opin Microbiol 9: 1-10. Beier, D., and Gross, R. (2006) The Bordetella virulence regulon controlled by the BvgAS two-component system. In: Bacterial Signal Transduction: Regulatory Networks and Drug Targeting. Ed.: Utsumi, R. Landes Bioscience, Georgetown USA, in press. Dominguez-Bernal, G., Müller-Altrock, S., Gonzalez-Zorn, B., Scortti, M., Herrmann, P., Monzo, H.J., Lacharme, L., Kreft J., and Vazquez-Boland, J.-A. (2006) A spontaneous genomic deletion in Listeria ivanovii identifies LIPI-2, a species-specific pathogenicity island encoding sphingomyelinase and numerous internalins. Mol Microbiol 59:415-432. Eisenreich, W., Slaghuis, J., Lauptiz, R., Bussemer, J., Stritzker, J., Schwarz, C., Schwarz, R., Dandekar, T., Goebel , W. and Bacher, A. (2006) 13C isotopolouge perturbation studies of Listeria monocytogenes carbon metabolism and its modulation by the virulence regulator PrfA. Proc Natl Acad Sci USA 103: 21040-2045. Feldhaar, H., Zientz, E., and Gross, R. (2006) Metabolic interactions between the carpenter ant Camponotus floridanus and its endosymbiont Blochmannia. Nova Acta Leopoldina, in press. Gaudermann, P., Vogl, I., Zientz, E., Silva, F., Moya, A., Gross, R., and Dandekar, T. (2006) Function predictions for conserved hypothetical proteins and proteins with putative function in Blochmannia floridanus. BMC Microbiol 6:1-15. Gentschev, I., Fensterle, J., Schmidt, A., Potapenko ,T., Troppmair, J, Goebel , W., Rapp, U.R. (2005) Use of a recombinant Salmonella enterica serovar Typhimurium strain expressing C-Raf for protection agains C-Raf induced lung adenoma in mice. BMC Cancer 9:15. Goebel, W. and Lory, S. (2006) Prokaryotic cell regulation Curr Opin Microbiol 9:123-126. Gopal, S., Borovok, I., Ofer, A., Yanku, M., Cohen, G., Goebel, W., Kreft, J., and Aharonowitz, Y. (2005) A multidomain fusion protein in Listeria monocytogenes catalyzes the two primary activities for glutathione biosynthesis. J Bacteriol 187:3839- 3847. Gottschalk, G., Goebel, W. and Pühler, A. (2006) Aspects of prokaryotic genome research. J Biotechnol 126: 1-2. Gross, R., Zientz, E., and Feldhaar, H. (2006) Intrazelluläre bakterielle Endosymbiosen in Insekten. BioSpektrum 12: 23-25. Hain, T., Steinweg, C., Kuenne, C.T., Billion, A., Ghai, R., Chatterjee, S.S., Domann, E., Kärst, U., Goesmann, A., Bekel, T., Bartels, D., Kaiser, O., Meyer, F., Pühler, A., Weisshaar, B., Wehland, J., Liang, C., Dandekar, T., Lampidis, R., Kreft, J., Goebel, W., and Chakraborty, T. (2006) Whole-genome sequence of Listeria welshimeri reveals common steps in genome reduction with Listeria innocua as compared to Listeria monocytogenes. J Bacteriol 188:7405-7415. Horvat, A., and Gross, R. (2006) Molecular characterisation of the BvgA response regulator of Bordetella holmesii. Microbiol Res, in press. Jiménez-Pearson, M.-A., Delany, I., Scarlato, V., and Beier, D. (2005) Phosphate flow in the chemotactic response system of Helicobacter pylori. Microbiology 151: 3299-3311. Jiménez-Pearson, M.-A., Dietz, P., and Beier, D. (2005) Protein-protein interaction of HP137 with histidine kinase HP244 does not contribute to flagellar regulation in Helicobacter pylori. Microbiol Res 166: 299-305. Joseph, B., and Beier, D. (2006) Global analysis of two-component gene regulation in Helicobacter pylori by mutation analysis and transcriptional profiling. Methods Enzymol, in press. Joseph, B., Przybilla, K., Stuhler, C., Schauer, K., Slaghuis ,J., Fuchs, T.M. and Goebel, W. (2006) Identifcation of Listeria monocytgenes genes contributing to intracellular regplation by expression profiling and mutant screening. J Bacteriol 188: 556-568.

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Löffler, D.I , Schoen, C.,U. Goebel, W. and Pilgrim S. (2006) Comparison of different live vaccine strategies in vivo for delivery of protein antigen or antigen-encoding DNA and mRNA by virulence-attenuated Listeria monocytogenes. Infect Immun 74: 3946-3957. Luo, Q., Herler, M., Müller-Altrock, S. and Goebel, W. (2005) Supportive and inhibitory elements for a putative PrfA-dependent promoter in Listeria mónocytogenes. Mol Microbiol 55: 986-997. Marr, A.K., Joseph, B., Mertins, S., Ecke, R., Müller-Altrock, S. and Goebel, W. (2006) Overexpression of PrfA leads to growth inhibition of Listeria monocytogenes in glucose-containing culture media by interfering with glucose uptake. J Bacteriol 188: 3887-3901. Mauder, N., Ecke, R., Mertins, S., Loeffler, D.I., Seidel, G., Sprehe, M., Hillen, W., Goebel, W. and Müller-Altrock S. (2006) Species-specific differences in the activity of PrfA, the key regulator of listerial virulence genes. J Bacteriol [Epub ahead of print] Middendorf, B., Stübs, D., Guiso, N., Deppisch, H., Gross, R., and Fuchs, T.M. (2005) Phg, a novel member of the autotransporter family present in Bordetella species. Microbiol Res 160: 329-336.

Müller, S., Förster, J., and Beier, D. (2006) Repeated sequence motifs in the Helicobacter pylori P1408 promoter do not affect its transcription. Microbiol Res 161: 212-221. Müller, S., Pflock, M., Schär, J., Kennard, S., and Beier, D. (2006) Regulation of expression of atypical orphan response regulators of Helicobacter pylori. Microbiol Res, in press. Pflock, M., Finsterer, N., Joseph, B., Mollenkopf, H., Meyer, T.F., and Beier, D. (2006) Characterization of the ArsRS regulon of Helicobacter pylori involved in acid adaptation. J Bacteriol 188: 3449-3462. Pflock, M., Kennard, S., Delany, I., Scarlato, V., and Beier, D. (2005) Acid-induced activation of the urease promoters is mediated directly by the ArsRS two-component system of Helicobacter pylori. Infect Immun 73: 6437-6445. Pflock, M., Kennard, S., Finsterer, N., and Beier, D. (2006) Acid-responsive gene regulation in the human pathogen Helicobacter pylori. J Biotechnol 126: 52-60. Rauch, M., Luo, Q., Müller-Altrock, S., and Goebel, W. (2005) SigB-dependent in vitro transcription of prfA and some newly identified genes of Listeria monocytogenes whose expression is affected by PrfA in vivo. J Bacteriol 187: 800-804. Schär, J., Sickmann, A., and Beier, D. (2005) Phosphorylation-independent activity of atypical response regulators of Helicobacter pylori. J Bacteriol 187: 3100-3109. Schmaußer, B., Endrich, S., Brändlein, S., Schär, J., Beier, D., Müller-Hermelink, H.-K., and Eck, M. (2005) The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, H. pylori gastritis, gastric carcinoma and its precursor lesions and upregulated by H. pylori. Clin Exp Immunol 139: 323-327. Schmid, M.W., Ng, E.Y., Lampidis, R., Emmerth, M., Walcher, M., Kreft, J., Goebel, W., Wagner, M., and Schleifer, K.H. (2005) Evolutionary history of the genus Listeria and its virulence genes. Syst Appl Microbiol 28:1-18. Schoen, C., Kolb-Mäurer, A., Geginat, G., Löffler, D., Bergmann, B., Stritzker, J., Szalay, A.A., Pilgrim, S. and Goebel, W. (2005) Bacterial delivery of functional messenger RNA to mammalian cells. Cell Microbiol 7: 709-724. Stoll, S., Gadau, J., Gross, R., and Feldhaar, H. (2006) Comparative phylogenetic diversity of the bacterial community associated with ants of the genus Tetraponera. Biol. J. Lin. Soc., in press. Stritzker, J., Schoen, C. and Goebel, W. (2005) Enhanced synthesis of internalin A in aro mutants of Listeria monocytogenes indicates posttranscriptional control of the inlAB mRNA. J Bacteriol 187: 2836-2845. Stübs, D., Fuchs, T.M., Schneider, B., Bosserhoff, A., and Gross, R. (2005) Identification and regulation of cold inducible factors of Bordetella bronchiseptica. Microbiology 151: 1895-1909. Williams, T., Bauer, S., Beier, D., and Kuhn, M. (2005) Construction and characterization of Listeria monocytogenes mutants with in-frame deletions in the response regulator genes identified in the genome sequence. Infect Immun 73: 3152- 3159. Williams, T., Joseph, B., Beier, D., Goebel, W., and Kuhn, M. (2005) Response regulator DegU of Listeria monocytogenes regulates the expression of flagella-specific genes. FEMS Microbiol Lett 252: 287-298. Zientz, E., Beyaert, I., Gross, R. and Feldhaar, H. (2006) Relevance of the endosymbiosis of Blochmannia floridanus and carpenter ants at different stages of the life cycle of the host. Appl Env Microbiol 72: 6027-6033. Zientz, E., Feldhaar, H., Stoll, S., and Gross, R. (2005) Insights into the microbial world associated with ants. Arch Microbiol 184:199-206.

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3-5 Institute of Molecular Infection Biology:

Agerer, F., S. Lux, A. Michel, M. Rohde, K. Ohlsen, and C. R. Hauck. (2006) Cellular invasion by Staphylococcus aureus reveals a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation. J. Cell Sci. 118:2189- 2200. Albert C, Jacobi S, De Buck E, Lammertyn E, Heuner K. (2006) Identification of target proteins of the Lss secretion system of Legionella pneumophila Corby. In Legionella: State of the art 30 years after its recognition, N.P.Cianciotto, Y.Abu Kwaik, P.H.Edelstein, B.S.Fields, D.F.Geary, T.G.Harrison, C.A.Joseph, R.M.Ratcliff, J.E.Stout, and M.S.Swanson, eds. (Washing- ton, D.C.: ASM Press), pp. 221-223. Alpert, C., Engst, W., Gühler, A., Oelschlaeger, T.A., and Blaut, M. (2005) Bacterial response to eukaryotic cells: analysis of differentially expressed proteins using nano liquid chromatography-electrospray ionization tandem mass spectrometry. J Chromatography 1082: 25-32. Appeldoorn, C.C.M., Joosten, J.A.F., Ait el Maate, F., Dobrindt, U., Hacker, J., Liskamp, R.M.J., Khan, A.S., Pieters, R.J. (2005) Novel multivalent mannose compounds and their inhibition of the adhesion of type 1 fimbriated uropathogenic E. coli. Tetrahedron: Asymmetry 16:361-372. Bader, T., Schröppel, K., Bentink, S., Agabian, N., Köhler, G., and Morschhäuser, J. (2006) Role of calcineurin in stress resistance, morphogenesis, and virulence of a Candida albicans wild-type strain. Infect Immun 74: 4366-4369. Batzilla CF, Rachid S, Engelmann S, Hecker M, Hacker J, Ziebuhr W. (2006) Impact of the accessory gene regulatory system (Agr) on extracellular proteins, codY expression and amino acid metabolism in Staphylococcus epidermidis.Proteomics. Jun;6(12):3602-13. Beloin, C., Michaelis, K., Lindner, K., Landani, P., Hacker, J., Ghigo, J.M., Dobrindt, U. (2006) The transcriptional antiterminator RfaH rpresses biofilm formation in Escherichia coli. J. Bacteriol., 188,1316 – 1331. Biswas, K., and Morschhäuser, J. (2005) The Mep2p ammonium permease controls nitrogen starvation-induced filamentous growth in Candida albicans. Mol Microbiol 56: 649-669. Blumer, C., Kleefeld, A., Lehnen, D., Heintz, M., Dobrindt, U., Nagy, G., Michaelis, K., Emödy, L., Polen, T., Rachel, R., Wendisch, V., Unden, G. (2005) Regulation of type 1 fimbriae synthesis and biofilm formation by the transcriptional regulator LrhA of Escherichia coli. Microbiology 151: 3287-3298. Braun, B.R., van het Hoog, M., d’Enfert, C., Martchenko, M., Dungan, J., Kuo, A., Inglis, D.O., Uhl, M.A., Hogues, H., Berriman, M., Lorenz, M., Levitin, A., Oberholzer, U., Bachewitch, C., Harcus, D., Marcil, A., Dignard, D., Iouk, T., Zito, R., Frangeul, L., Tekaia, F., Rutherford, K., Wang, E., Munro, C.A., Bates, S., Gow, N.A., Hoyer, L., Köhler, G., Morschhäuser, J., Newport, G., Znaidi, S., Raymond, M., Turcotte, B., Sherlock, G., Costanzo, M., Ihmels, J., Berman, J., Sanglard, D., Agabian, N., Mitchell, A.P., Johnson, A.D., Whiteway, M., and Nantel, A. (2005) A human-curated annotation of the Candida albicans genome. PloS Genetics 1: 36-57. Bringmann, G., I. Kajahn, M. Reichert, S. E. H. Pedersen, J. H. Faber, T. Gulder, R. Brun, S. B. Christensen, A. Ponte-Sucre, H. Moll, G. Heubl and V. Mudogo (2007). Ancistrocladinium A and B, the First N,C-Coupled Naphthyldihydroisoquinoline Alkaloids, from a Congolese Ancistrocladus Species. J. Org. Chem. (in press). Brüggemann H, Hagman A, Jules M, Sismeiro O, Dillies M-A, Gouyette C, Kunst F, Steinert M, Heuner K, Coppée J-Y, Buchrieser C. (2006) Virulence strategies for infecting phagocytes deduced from the transcriptional program of Legionella pneumophila. Cell. Microbiol. 8:1228-1240. Brzuszkiewics, E., Brüggemann, H., Liesegang, H., Emmerth, M., Ölschläger, T., Nagy, G., Albermann, K., Wagner, C., Buchrieser, C., Emödy, L., Gottschalk, G., Hacker, J. and Dobrindt, U. (2006) How to become a uropathogen: Comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains. Proc Natl Acad Sci USA 103: 12879-12884. Coste, A., Turner, V., Ischer, F., Morschhäuser, J., Forche, A., Selmecki, A., Berman, J., Bille, J., and Sanglard, D. (2006) A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172: 2139-2156. Dobrindt, U. (2005). (Patho-)Genomics of E. coli. Int. J. Med. Microbiol. 295:357-371. Dobrindt, U., Hacker, J. (2005) (Patho-)Genomics of Escherichia coli and Shigella. In: Pathogenomics (J. Hacker, U. Dobrindt, eds.) Wiley-VCH, Weinsheim, 85-108. Dobrindt, U., Hacker, J. (2005) Plasmids, Phages and Pathogenicity islands in relation with bacterial protein toxins: Impact on the evolution of microbes. In: Bacterial protein toxins: A sourcebook, 3. Edition (J. Alouf, M. Popoff, eds.), Elsevier Ltd. Engel, D., Dobrindt, U., Tittel, A., Peters, P., Maurer, J., Gütgermann, I., Kaissling, B., Kuziel, W., Jung, S., and Kurts, C. (2006) TNF{alpha}/iNOS-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection, but are dispensable for bacterial clearance. Infect. Immun. 74: 6100-6107. Farbrother, P., Wagner, C., Na, J., Tunggal, B., Morio, T., Urshihara, H., Tanaka, Y., Schleicher, M., Steinert, M., Eichinger, L. (2006) Dictyostelium transcriptional host cell response upon infection with Legionella. Cell. Microbiol. 8. 438-56. Gaur, N.A., Manoharlal, R., Saini, P., Prasad, T., Mukhopadhyay, G., Hoefer, M, Morschhäuser, J., and Prasad, R. (2005) Ex-

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pression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory element. Biochem Biophys Res Commun 332: 206-214. Germon, P., Roche, D., Melo, S., Mignon-Grasteau, S., Dobrindt, U., Hacker, J., Schouler, C., Moulin-Schouleur, M. (2006) Relationships between phylogenetic groups, ecto-chromosomal DNA insertion hot-spots and the integrity of tDNA loci in the genome of Escherichia coli strains. Microbiology, accepted for publication. Hacker, J. (2006) Warum Bakterien krank machen – Zur Molekularbiologie bakterieller Pathogenitätsmechanismen. Nord- rhein-Westfälische Akademie der Wissenschaften, Vorträge, Reihe N, 471, 1 – 36. Hacker, J., Dobrindt, U., Gottschalk, G., Brüggemann, H., Carniel, E., Buchrieser, C., Middendorf, B., B. Hochhut, B. (2005). Analysis of Infectious Agents and the Concept of Pathogenicity Islands. Nova Acta Leopoldina 344:61-65. Hacker, J., Dobrindt, U., Steinert, M., Merkert, H., Hentschel, U. (2005) Co-evolution of bacteria and their hosts: A marriage made in heaven or hell? In: The Influence of cooperative bacteria on their animal host biology (M. J. McFall-Ngai, B. Henderson, E. G. Ruby, eds.), Cambridge University Press, Cambridge, 57-72. Hammerschmidt, S., Hacker, J., Klenk, H.D. (2005) Threat of Infection: Microbes of high pathogenic potential strategies of detection, control and eradication. Int. J. Med. Microbiol. 295, 141 – 151. Harraghy, N., J. Kormanec, C. Wolz, D. Homerova, C. Goerke, K. Ohlsen, S. Qazi, P. Hill, and M. Herrmann. (2006) sae is essential for expression of the staphylococcal adhesins Eap and Emp. Microbiology 151:1789-1800. Hauck, C. R., and K. Ohlsen. (2006) Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Curr. Opin. Microbiol. 9:1-7. Hechard, Y., Ferraz, S., Bruneteau, E., Steinert, M., Berjeaud, J.-M. (2005) Isolation and characterization of a Staphylococcus warneri strain producing an anti-Legionella peptide. FEMS Microbiol. Lett. 252: 19-23. Hejnova, J., Dobrindt, U., Nemcova, R., Rusniok, C., Bomba, A., Frangeul, L., Hacker, J., Glaser, P., Buchrieser, C., Šebo, P. (2005) Characterization of the flexible genome complement of the probiotic Escherichia coli strain A0 34/86 (O83:K24:H31). Microbiology 151: 385-398. Hentschel, U., Ölschläger, T., Dobrindt, U., Hacker, J. (2005) Mechanisms of Destruction and Healing in Ecosystems: A Microbiologist’s View. Nova Acta Leopoldina, 343, 121 – 126. Heuner K, Jacobi S, Albert C, Steinert M, Brüggemann H, Buchrieser C. (2006). Gene Expression and Virulence in Legionella: The Flagellar Regulon. In Legionella: State of the art 30 years after its recognition, N.P.Cianciotto, Y.Abu Kwaik, P.H.Edelstein, B.S.Fields, D.F.Geary, T.G.Harrison, C.A.Joseph, R.M.Ratcliff, J.E.Stout, and M.S.Swanson, eds. (Washington, D.C.: ASM Press), pp. 327-332. Hiller, D., Sanglard, D., and Morschhäuser, J. (2006) Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans. Antimicrob Agents Chemother 50: 1365-1371. Hiller, D., Stahl, S., and Morschhäuser, J. (2006) Multiple cis-acting sequences mediate upregulation of the MDR1 efflux pump in a fluconazole-resistant, clinical Candida albicans isolate. Antimicrob Agents Chemother 50: 2300-2308. Hochhut, B., Dobrindt, U., Hacker, J. (2005) Pathogenicity islands and their role in bacterial virulence and survival. Contrib. Microbiol., 12, 234 – 254. Hochhut, B., Dobrindt, U., Hacker, J. (2006) Pathogenicity islands. In: Evolution of microbial pathogens (H. Seifert, V. di Rita, eds.) ASM Press, Washington D.C. 83-107. Hochhut, B., Wilde, C., Balling, G., Middendorf, B., Dobrindt, U., Brzuszkiewicz, E., Gottschalk, G., Carniel, E., Hacker, J. (2006) Role of pathogenicity island-associated integrases in the genome plasticity of uropathogenic Escherichia coli strain 536. Mol. Microbiol. 61: 584-595. Holden, N. J., Totsika, M., Mahler, E., Roe, A. J., Catherwood, K., Lindner, K., Dobrindt, U., Gally, D. L. (2006) Demonstration of regulatory cross-talk between P-fimbriae and type 1 fimbriae in uropathogenic Escherichia coli. Microbiology 152: 1143- 1153. Horstmann, M., Ehses, P., Schweimer, K., Steinert, M., Kamphausen, T., Fischer, G.,Hacker, J., Rosch, P., Faber, C. (2006) Domain Motions of the Mip Protein from Legionella pneumophila. Biochemistry. 45, 12303-12311. Horstmann, M., Kamphausen, T., Schweimer, K., Steinert, M., Hacker, J., Haase, A., Rösch, P., Fischer, G., Faber, C. (2005) 1H, 13C, 15N backbone and sidechain resonance assignment of Mip(77-213) the PPIase domain of the Legionella pneumophila Mip protein. J. Biomol. NMR. 31: 77-78. Janka, A., Becker, G., Sonntag, A.-K., Bielaszewska, M., Dobrindt, U., Karch, H., (2005) Presence and Characterization of a Mosaic Genomic Island Which Distinguishes Sorbitol-Fermenting Enterohemorrhagic Escherichia coli O157:H- from E. coli O157:H7. Appl. Environ. Microbiol. 71: 4875-4878. K. Ohlsen and J. Hacker. Infections in the elderly. (2006) Int. J. Med. Microbiol. 294:471-472. Körner, U., V. Fuss, J. Steigerwald and H. Moll (2006). The biogenesis of Leishmania major-harboring vacuoles in dendritic cells. Infect. Immun. 74: 1305-1312. Kouokam, J. C., Nyunt Wai, S., Dobrindt, U., Hacker, J., Uhlin, B. E. (2006) Active cytotoxic necrotizing factor 1 associated with outer membrane vesicles from uropathogenic E. coli. Infect. Immun. 74: 2022-2030. Kozitskaya S, Olson ME, Fey PD, Witte W, Ohlsen K, Ziebuhr W. (2005) Clonal analysis of Staphylococcus epidermidis isolates

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carrying or lacking biofilm-mediating genes by multilocus sequence typing. J Clin Microbiol. 43 4751-7. Michel, A., Agerer, F., Hauck, C.F., Herrmann, M., Ullrich, J., Hacker, J., Ohlsen, K. (2006) Global regulatory impact of ClpP protease of Staphylococcus aureus on regulons involved in virulence, oxidative stress response, autolysis, and DNA repair. J. Bacteriol., 188, 5783-5796. Moll, H. (2006). Dendritic cells in leishmaniasis: Regulators of immunity and tool for new immune intervention strategies. In: Handbook of Dendritic Cells – Biology, Diseases and Therapies, M. B. Lutz, A. Steinkasserer and N. Romani (eds.), Wiley- VCH, Weinheim, Germany, pp. 669-691. Morschhäuser, J., Staib, P., and Köhler, G. (2005) CARE-2 fingerprinting of Candida albicans isolates. Methods Mol Med 118: 27-34. Morschhäuser, J., Staib, P., and Köhler, G. (2005) Targeted gene deletion in Candida albicans wild-type strains by MPAR- flipping. Methods Mol Med 118: 35-44. Müller, C. M., Dobrindt, U., Nagy, G., Emödy, L., Uhlin, B.E., Hacker, J. (2006) Role of Histone-like Proteins H-NS and StpA in Expression of Virulence Determinants of uropathogenic Escherichia coli. J. Bacteriol. 188: 5428-5438. Nougayrède, J.-P., Homburg, S., Taieb, F., Boury, M., Brzuszkiewicz, E., Gottschalk, G., Buchrieser, C., Hacker, J., Dobrindt, and U., Oswald, E. (2006) Escherichia coli induces DNA double strand breaks in eukaryotic cells. Science 313:848-851. Nagy, G., Dobrindt, U., Grozdanov, L., Hacker, J., and Emody, L. (2005) Transcriptional regulation through RfaH contributes to intestinal colonization by Escherichia coli. FEMS Microbiol Lett 244: 173-180. Nagy, G., Altenhoefer, A., Knapp, O., Maier, E., Dobrindt, U., Blum-Oehler, G., Benz, R., Emody, L., and Hacker, J. (2006) Both alpha-haemolysin determinants contribute to full virulence of uropathogenic Escherichia coli strain 536. Microbes Infect 8: 2006-2012. Nagy, G., Danino, V., Dobrindt, U., Pallen, M., Chaudhuri, R., Emody, L., Hinton, J.C., and Hacker, J. (2006) Down-regulation of key virulence factors makes the Salmonella enterica serovar Typhimurium rfaH mutant a promising live-attenuated vaccine candidate. Infect Immun 74: 5914-5925. Streker K., Freiberg, C., Labischinski, H., Hacker, J, Ohlsen K. (2005) Staphylococcus aureus NfrA (SA0367) is a flavin mononucleotide-dependent NADPH oxidase involved in oxidative stress response. J Bacteriol. 187, 2249-2256. Taylor, B., Staib, P., Binder, A., Biesemeier, A., Sehnal, M., Röllinghoff, M., Morschhäuser, J., and Schröppel, K. (2005) Profile of Candida albicans-secreted aspartic proteinase elicited during vaginal infection. Infect Immun 73: 1828-1835. Theiss, S., Ishdorj, G., Brenot, A., Kretschmar, M., Lan, C.Y., Nichterlein, T., Hacker, J., Nigam. S., Agabian, N., Kohler, G.A. (2006) Inactivation of the phospholipase B gene PLB5 in wild-type Candida albicans reduces cell-associated phospholipase A(2) activity and attenuates virulence. Int J Med Microbiol. 296, 405-420. Trujillo-Vargas, C. M., J. R. Ramírez-Pineda, A. Palmetshofer, S. Grunewald, H. Moll, C. Berberich and K. J. Erb (2005). Mice vaccinated with allergen-pulsed myeloid dendritic cells are not protected from developing allergen-induced Th2 responses. Int. Arch. Allergy Immunol. 137: 219-228. Vicik, R., V. Hoerr, M. Glaser, M. Schultheis, E. Hansell, J. H. McKerrow, U. Holzgrabe, C. R. Caffrey, A. Ponte-Sucre, H. Moll, A. Stich and T. Schirmeister (2006). Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypano- soma brucei as lead trypanocidal agents. Bioorg. Med. Chem. Letters 16: 2753-2757. Ziebuhr W, Hennig S, Eckart M, Kranzler H, Batzilla C, Kozitskaya S. (2006) Nosocomial infections by Staphylococcus epidermidis: how a commensal bacterium turns into a pathogen. Int J Antimicrob Agents. 2006 Aug;28 Suppl 1:S14-20. Epub Jul 7.

3-6 Institute of Pathology : Adam, P., Katzenberger, T., Eifert, M., Ott, M.M., Rosenwald, A., Muller-Hermelink, H.K., and Ott, G. (2005) Presence of preserved reactive germinal centers in follicular lymphoma is a strong histopathologic indicator of limited disease stage. Am J Surg Pathol 29: 1661-1664. Adam, P., Zettl, A., Zollner, U., Dietl, J., Muller-Hermelink, H.K., and Eck, M. (2005) Metastasizing vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation: genetic evidence of clonal origin. Hum Pathol 36: 1143-1147. Adam, P., Steinlein, C., Schmid, M., Haralambieva, E., Stocklein, H., Leich, E., Rosenwald, A., Muller-Hermelink, H.K., and Ott, G. (2006) Characterization of chromosomal aberrations in diffuse large B-cell lymphoma (DLBL) by G-banding and spectral karyotyping (SKY). Cytogenet Genome Res 114: 274-278. Ballova, V., Ruffer, J.U., Haverkamp, H., Pfistner, B., Muller-Hermelink, H.K., Duhmke, E., Worst, P., Wilhelmy, M., Naumann, R., Hentrich, M., Eich, H.T., Josting, A., Loffler, M., Diehl, V., and Engert, A. (2005) A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16: 124-131. Bea, S., Zettl, A., Wright, G., Salaverria, I., Jehn, P., Moreno, V., Burek, C., Ott, G., Puig, X., Yang, L., Lopez-Guillermo, A., Chan, W.C., Greiner, T.C., Weisenburger, D.D., Armitage, J.O., Gascoyne, R.D., Connors, J.M., Grogan, T.M., Braziel, R., Fisher, R.I., Smeland, E.B., Kvaloy, S., Holte, H., Delabie, J., Simon, R., Powell, J., Wilson, W.H., Jaffe, E.S., Montserrat, E., Muller-

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Hermelink, H.K., Staudt, L.M., Campo, E., and Rosenwald, A. (2005) Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106: 3183-3190. Brighenti, A., Andrulis, M., Geissinger, E., Roth, S., Muller-Hermelink, H.K., and Rudiger, T. (2005) Extrafollicular proliferation of B cells in the absence of follicular hyperplasia: a distinct reaction pattern in lymph nodes correlated with primary or recall type responses. Histopathology 47: 90-100. Cejkova, P., Zettl, A., Baumgartner, A.K., Chott, A., Ott, G., Muller-Hermelink, H.K., and Starostik, P. (2005) Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch 446: 416-420. Chanudet, E., Zhou, Y., Bacon, C.M., Wotherspoon, A.C., Muller-Hermelink, H.K., Adam, P., Dong, H.Y., de Jong, D., Li, Y., Wei, R., Gong, X., Wu, Q., Ranaldi, R., Goteri, G., Pileri, S.A., Ye, H., Hamoudi, R.A., Liu, H., Radford, J., and Du, M.Q. (2006) Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J Pathol 209: 344-351. Chuang, W.Y., Strobel, P., Gold, R., Nix, W., Schalke, B., Kiefer, R., Opitz, A., Klinker, E., Muller-Hermelink, H.K., and Marx, A. (2005) A CTLA4high genotype is associated with myasthenia gravis in thymoma patients. Ann Neurol 58: 644-648. Dave, S.S., Fu, K., Wright, G.W., Lam, L.T., Kluin, P., Boerma, E.J., Greiner, T.C., Weisenburger, D.D., Rosenwald, A., Ott, G., Muller-Hermelink, H.K., Gascoyne, R.D., Delabie, J., Rimsza, L.M., Braziel, R.M., Grogan, T.M., Campo, E., Jaffe, E.S., Dave, B.J., Sanger, W., Bast, M., Vose, J.M., Armitage, J.O., Connors, J.M., Smeland, E.B., Kvaloy, S., Holte, H., Fisher, R.I., Miller, T.P., Montserrat, E., Wilson, W.H., Bahl, M., Zhao, H., Yang, L., Powell, J., Simon, R., Chan, W.C., and Staudt, L.M. (2006) Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med 354: 2431-2442. Engert, A., Ballova, V., Haverkamp, H., Pfistner, B., Josting, A., Duhmke, E., Muller-Hermelink, K., and Diehl, V. (2005) Hodgkin’s lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin’s Study Group. J Clin Oncol 23: 5052-5060. Fu, K., Weisenburger, D.D., Greiner, T.C., Dave, S., Wright, G., Rosenwald, A., Chiorazzi, M., Iqbal, J., Gesk, S., Siebert, R., De Jong, D., Jaffe, E.S., Wilson, W.H., Delabie, J., Ott, G., Dave, B.J., Sanger, W.G., Smith, L.M., Rimsza, L., Braziel, R.M., Muller-Hermelink, H.K., Campo, E., Gascoyne, R.D., Staudt, L.M., and Chan, W.C. (2005) Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood 106: 4315-4321. Gattenlohner, S., Bonengel, M., and Muller-Hermelink, H.K. (2006) [Optimized RT-PCR based detection of specific genetic abnormalities within malignant hematopoietic disorders]. Pathologe 27: 182-187. Gattenlohner, S., Marx, A., Markfort, B., Pscherer, S., Landmeier, S., Juergens, H., Muller-Hermelink, H.K., Matthews, I., Beeson, D., Vincent, A., and Rossig, C. (2006) Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor. Cancer Res 66: 24-28. Geissinger, E., Bonzheim, I., Krenacs, L., Roth, S., Strobel, P., Ott, G., Reimer, P., Wilhelm, M., Muller-Hermelink, H.K., and Rudiger, T. (2005) Identification of the tumor cells in peripheral T-cell lymphomas by combined polymerase chain reaction- based T-cell receptor beta spectrotyping and immunohistological detection with T-cell receptor beta chain variable region segment-specific antibodies. J Mol Diagn 7: 455-464. Geissinger, E., Adam, P., Muller-Hermelink, H.K., and Rudiger, T. (2006) [Cutaneous B-cell lymphoma: Classification and diagnostics.]. Pathologe. Geissinger, E., Bonzheim, I., Krenacs, L., Roth, S., Reimer, P., Wilhelm, M., Muller-Hermelink, H.K., and Rudiger, T. (2006) Nodal peripheral T-cell lymphomas correspond to distinct mature T-cell populations. J Pathol 210: 172-180. Girschick, H.J., Raab, P., Surbaum, S., Trusen, A., Kirschner, S., Schneider, P., Papadopoulos, T., Muller-Hermelink, H.K., and Lipsky, P.E. (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64: 279-285. Greiner, T.C., Dasgupta, C., Ho, V.V., Weisenburger, D.D., Smith, L.M., Lynch, J.C., Vose, J.M., Fu, K., Armitage, J.O., Braziel, R.M., Campo, E., Delabie, J., Gascoyne, R.D., Jaffe, E.S., Muller-Hermelink, H.K., Ott, G., Rosenwald, A., Staudt, L.M., Im, M.Y., Karaman, M.W., Pike, B.L., Chan, W.C., and Hacia, J.G. (2006) Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc Natl Acad Sci U S A 103: 2352-2357. Haralambieva, E., Boerma, E.J., van Imhoff, G.W., Rosati, S., Schuuring, E., Muller-Hermelink, H.K., Kluin, P.M., and Ott, G. (2005) Clinical, immunophenotypic, and genetic analysis of adult lymphomas with morphologic features of Burkitt lymphoma. Am J Surg Pathol 29: 1086-1094. Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., Muller- Hermelink, H.K., Banham, A.H., and Ott, G. (2006) Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. Leukemia 20: 1300-1303. Hummel, M., Bentink, S., Berger, H., Klapper, W., Wessendorf, S., Barth, T.F., Bernd, H.W., Cogliatti, S.B., Dierlamm, J., Feller, A.C., Hansmann, M.L., Haralambieva, E., Harder, L., Hasenclever, D., Kuhn, M., Lenze, D., Lichter, P., Martin-Subero, J.I., Moller, P., Muller-Hermelink, H.K., Ott, G., Parwaresch, R.M., Pott, C., Rosenwald, A., Rosolowski, M., Schwaenen, C., Sturzenhofecker, B., Szczepanowski, M., Trautmann, H., Wacker, H.H., Spang, R., Loeffler, M., Trumper, L., Stein, H., and Siebert, R. (2006) A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med 354:

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2419-2430. Iqbal, J., Neppalli, V.T., Wright, G., Dave, B.J., Horsman, D.E., Rosenwald, A., Lynch, J., Hans, C.P., Weisenburger, D.D., Greiner, T.C., Gascoyne, R.D., Campo, E., Ott, G., Muller-Hermelink, H.K., Delabie, J., Jaffe, E.S., Grogan, T.M., Connors, J.M., Vose, J.M., Armitage, J.O., Staudt, L.M., and Chan, W.C. (2006) BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24: 961-968. Katzenberger, T., Petzoldt, C., Holler, S., Mader, U., Kalla, J., Adam, P., Ott, M.M., Muller-Hermelink, H.K., Rosenwald, A., and Ott, G. (2006) The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 107: 3407. Muller-Hermelink, H.K. (2006). Pathologe. Nogova, L., Reineke, T., Eich, H.T., Josting, A., Muller-Hermelink, H.K., Wingbermuhle, K., Brillant, C., Gossmann, A., Oertel, J., Bollen, M.V., Muller, R.P., Diehl, V., and Engert, A. (2005) Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16: 1683-1687. Nogova, L., Reineke, T., Josting, A., Muller-Hermelink, H.K., Eich, H.T., Behringer, K., Muller, R.P., Diehl, V., and Engert, A. (2005) Lymphocyte-predominant and classical Hodgkin’s lymphoma—comparison of outcomes. Eur J Haematol Suppl: 106- 110. Rimsza, L.M., Roberts, R.A., Campo, E., Grogan, T.M., Bea, S., Salaverria, I., Zettl, A., Rosenwald, A., Ott, G., Muller-Hermelink, H.K., Delabie, J., Fisher, R.I., Unger, J.M., Leblanc, M., Staudt, L.M., Jaffe, E.S., Gascoyne, R.D., Chan, W.C., Weisenburger, D.D., Greiner, T., Braziel, R.M., and Miller, T.P. (2006) Loss of major histocompatibility class II expression in non-immune- privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions. Blood 107: 1101-1107. Roberts, R.A., Wright, G., Rosenwald, A.R., Jaramillo, M.A., Grogan, T.M., Miller, T.P., Frutiger, Y., Chan, W.C., Gascoyne, R.D., Ott, G., Muller-Hermelink, H.K., Staudt, L.M., and Rimsza, L.M. (2006) Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood 108: 311-318. Rudiger, T., Geissinger, E., and Muller-Hermelink, H.K. (2006) ‘Normal counterparts’ of nodal peripheral T-cell lymphoma. Hematol Oncol 24: 175-180. Rudiger, T., Zettl, A., Adam, P., Bonzheim, I., Geissinger, E., and Muller-Hermelink, H.K. (2006) [Peripheral NK/T-cell lymphoma.]. Pathologe. Schmausser, B., Andrulis, M., Endrich, S., Muller-Hermelink, H.K., and Eck, M. (2005) Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 295: 179-185. Schmausser, B., Endrich, S., Brandlein, S., Schar, J., Beier, D., Muller-Hermelink, H.K., and Eck, M. (2005) The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori. Clin Exp Immunol 139: 323-327. Sonnen, R., Schmidt, W.P., Muller-Hermelink, H.K., and Schmitz, N. (2005) The International Prognostic Index determines the outcome of patients with nodal mature T-cell lymphomas. Br J Haematol 129: 366-372. Strobel, P., Marino, M., Feuchtenberger, M., Rouziere, A.S., Tony, H.P., Wulbrand, U., Forster, R., Zettl, A., Lee Harris, N., Kreipe, H., Laeng, R.H., Muller-Hermelink, H.K., and Marx, A. (2005) Micronodular thymoma: an epithelial tumour with abnormal chemokine expression setting the stage for lymphoma development. J Pathol 207: 72-82. Strobel, P., Marx, A., Zettl, A., and Muller-Hermelink, H.K. (2005) Thymoma and thymic carcinoma: an update of the WHO Classification 2004. Surg Today 35: 805-811. van den Brandt, J., Kwon, S.H., McPherson, K.G., Petrovic, S., Zettl, A., Muller-Hermelink, H.K., and Reichardt, H.M. (2006) Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats. Eur J Immunol 36: 2223-2234. Zettl, A., Rudiger, T., Marx, A., Muller-Hermelink, H.K., and Ott, G. (2005) Composite marginal zone B-cell lymphoma and classical Hodgkin’s lymphoma: a clinicopathological study of 12 cases. Histopathology 46: 217-228.

3-7 Medical Clinic I, (in the field of Immunology and Infectiology):

Nahrendorf M, Hu K, Frantz S, Jaffer FA, Tung CH, Hiller KH, Voll S, Nordbeck P, Sosnovik D, Gattenlohner S, Novikov M, Dickneite G, Reed GL, Jakob P, Rosenzweig A, Bauer WR, Weissleder R, Ertl G (2006) Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation. 113(9):1196-202. Kuhlencordt P, Hötten S, Schödel J, Rützel S, Hu K, Widder J, Marx A, Huang PL, Ertl G (2006) Atheroprotective effects of neuronal nitric oxide synthase in apolipoprotein e knockout mice.Arterioscler Thromb Vasc Biol.26(7):1539-44. Bauersachs J, Thum T, Frantz S, Ertl G (2005) Cardiac regeneration by progenitor cells—bedside before bench? Eur J Clin Invest. 35(7):417-20

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3-8 Medical Clinic II, Clinical Infectiology (in the field of Immunology and Infectiology):

A. Benesic, M. Zilly, H. Klinker, P. Langmann (2005). HIV-protease4 inhibitors show no effects on viability and intracellular Ca2+ in human proximal tubular cells in primary culture. Eur J Med Res 10: 82 A. Bergk, P. Buggisch, C. Sarrazin, G. Teuber, H. Klinker, B. Wiedemann, T. Berg (2005). Der Nachweis einer minimalen Hepatitis C Virämie 12 Wochen nach Therapiebeginn ist mit einer hohen Relapserate assoziiert. Z Gastroenterol 43: 852 A. Helle, W. Heinz, V. Kunzmann, H. Klinker, H. Einsele (2006). Recurrent malignat schwannoma with an intracardial tumor manifestation: a case report. Onkologie 29 (Suppl 3): 149 A. Knipper, P. Langmann, M. Zilly, R. Winzer, H. Klinker (2005). Visceral leishmaniasis as a reason for tricytopenia under retroviral treatment of HIV-infection. Eur J Med Res 10: 105-106 A. Trein, P. Langmann, M. Zilly, H. Klinker, E. Schnaitmann (2005). Efficacy and safety of a combination of lopinavir and efavirenz or nevirapine in a nuke free regimen. Eur J Med Res 10: 80 B. Schöttker, W. Heinz, F. Weissinger, K. Sözener, M. Eck, J. Seufert (2006). Parathyroid Hormone-Related Protein-Associated Hypercalcemia in a Patient with CLL Type Low Grade Leukemic B-Cell Lymphoma. Haematologica/the hematology journal; 91 (online) Beck O, Topp MS, Koehl U, Roilides E, Simitsopoulou M, Hanisch M, Sarfati J, Latge JP, Klingebiel T, Einsele H, Lehrnbecher T. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus. Blood. 2006 Mar 15;107(6):2562-9.. Bethge WA, Schmalzing M, Stuhler G, Schumacher U, Krober SM, Horger M, Einsele H, Kanz L, Hebart H. Mucormycoses in patients with hematologic malignancies: an emerging fungal infection. Haematologica. 2005 Bissinger AL, Brugger J, Grigoleit GU, Grundemann C, Hebart H, Einsele H, Jahn G. Visualization and microscopic quantification of HCMV-peptide-specific cytotoxic T lymphocytes using tetramer binding. Viral Immunol. 2005;18(3):534- 8 Bissinger AL, Einsele H, Hamprecht K, Schumacher U, Kandolf R, Loeffler J, Aepinus C, Bock T, Jahn G, Hebart H. Infectious pulmonary complications after stem cell transplantation or chemotherapy: diagnostic yield of bronchoalveolar lavage. Diagn Microbiol Infect Dis. 2005 Aug;52(4):275-80 Brodoefel H, Vogel M, Hebart H, Einsele H, Vonthein R, Claussen C, Horger M. Long-term CT follow-up in 40 non-HIV immunocompromised patients with invasive pulmonary aspergillosis: kinetics of CT morphology and correlation with clinical findings and outcome. AJR Am J Roentgenol. 2006 Aug;187(2):404-13. Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, Juliusson G, Ahlberg L, Nagler A, Shimoni A, Sureda A, Boiron JM, Einsele H, Chopra R, Carella A, Cavenagh J, Gratwohl A, Garban F, Zander A, Bjorkstrand B, Niederwieser D, Gahrton G, Apperley JF. Outcomes for reduced intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the chronic leukemia working party of the EBMT. Blood. 2005 Jun 1;105(11):4532-9. D. Tappe, R. Winzer, P. Ströbel, A. Stich, H. Klinker, M. Frosch (2006). Linguatuliasis in Germany. Emerging Infectious Diseases 12: 1034-1036 Daikeler T, Erley C, Mohren M, Amberger C, Einsele H, Kanz L, Kotter I.Fever and increasing cANCA titre after kidney and autologous stem cell transplantation for Wegener’s granulomatosis. Ann Rheum Dis. 2005 Apr;64(4):646-7 E. Schott, H. Witt, G. Teuber, C. Sarrazin, H. Klinker, P. Buggisch, B. Wiedenmann, T. Berg (2005). Assoziation von Single Nukleotide Polymorphismen (SNPs) des cytotoxic T lmphocyte antigene-4 (CTLA-4) Gens mit dem Ansprechen auf eine PegInterferon-alpha2b/Ribavirin Kombinationstherapie bei Patienten mit chronischer Hepatitis C (HCV-)-Infektion. Z Gastroenterol 43: 840 Einsele H. T-cell therapy for viral and fungal infections. Blood 2005, 106(13) Einsele H., Pierre Reusser, Martin Bornhäuser, Peter Kalhs, Gerhard Ehninger, Holger Hebart, Yves Chalandon, Nicolaus Kröger, Bernd Hertenstein, Frank Rohde.Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation.Blood. 2006 Apr 1;107(7):3002-8 Graham J, Einsele H, Moreau P, San Miguel J. Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. Cancer Treatment Reviews, Volume 31, Issue 8, December 2005, Pages 591-602 Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, Einsele H, Cordonnier C; Acute and Chronic Leukemia Working Parties; Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005 Nov;36(9):757-69 H. Klinker (2005). Pharmakologische Interaktionen bei der antiretroviralen Therapie. Arzneimitteltherapie 23: 80-88 H. Klinker (2005). Therapie der chronischen Hepatitis C: Was ist bei „Problempatienten“ zu beachten? Klinikarzt 34: 140- 145

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H. Klinker (2006). Ribavirinspiegelmessung – Pro und Contra aus klinischer Sicht. In: J. Rockstroh, S. Mauss, H. Jäger (Hrsg.): Koinfektion Hepatitis und HIV, Band 4, Georg Thieme Verlag Stuttgart New York, S. 85-88 H. Klinker, P. Langmann, R. Winzer (2006). Oft kombiniert, wenig untersucht - Proteasehemmer und Interaktionen. In: C. Hoffmann, H. Jäger (Hrsg.): AIDS-Monographien, Band 11, „AIDS 2006: Wunschwelt Heilung – Evidenz für Fortschritt oder Stillstand?“, 178-182 Horger M, Einsele H, Schumacher U, Wehrmann M, Hebart H, Lengerke C, Vonthein R, Claussen CD, Pfannenberg C. Invasive pulmonary aspergillosis: frequency and meaning of the „hypodense sign“ on unenhanced CT. Br J Radiol. 2005 Aug;78(932):697-703 Horger M, Hebart H, Einsele H, Lengerke C, Claussen CD, Vonthein R, Pfannenberg C. Initial CT manifestations of invasive pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? Eur J Radiol. 2005 Sep;55(3):437-44 Horger M, Lengerke C, Pfannenberg C, Wehrmann M, Einsele H, Knop S, Claussen CD. Significance of the „halo“ sign for progression and regression of nodular pulmonary amyloidosis: radiographic-pathological correlation (2005:6b).Eur Radiol. 2005 Sep;15(9):2037-40 J. Halangk, H. Witt, C. Sarrazin, G. Puhl, G. Teuber, H. Klinker, P. Buggisch, H. Hinrichsen, V. Weich, A. Bergk, B. Wiedenmann, P. Neuheus, W. Luck, T. Berg (2006). Bedeutung von Polymorphismen des Komplementfaktor 5 auf die Fibroseprogression bei chronischen Lebererkrankungen. Z Gastroenterol 44: 83 Karthaus M, Hebart H, Einsele H, Schaefer H, Scheel-Walter H, Buchheidt D, Lehrnbecher T. Long-term survival in patients with acute leukemia and chronic disseminated candidiasis despite minimal antileukemic therapy. Haematologica. 2006 Oct;91(10):1422-3. Kruger WH, Bohlius J, Cornely OA, Einsele H, Hebart H, Massenkeil G, Schuttrumpf S, Silling G, Ullmann AJ, Waldschmidt DT, Wolf HH. Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases working party (AGIHO) of the german society of haematology and oncology. Ann Oncol. 2005 Aug;16(8):1381-90 Lengerke C, Ljubicic T, Meisner C, Loeffler J, Sinzger C, Einsele H, Hebart H. Evaluation of the COBAS Amplicor HCMV Monitor for early detection and monitoring of human cytomegalovirus infection after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006 Jul;38(1):53-60 Liebisch P, Scheck D, Erne SA, Wellmann A, Wendl C, Janczik S, Kolmus S, Krober A, Einsele H, Straka C, Goldschmidt H, Benner A, Stilgenbauer S, Dohner H. Duplication of chromosome arms 9q and 11q: evidence for a novel, 14q32 translocation-independent pathogenetic pathway in multiple myeloma.Genes Chromosomes Cancer. 2005 Jan;42(1):78- 81 Ljungman P, Engelhard D, de la Camara R, Einsele H, Locasciulli A, Martino R, Ribaud P, Ward K, Cordonnier C; Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 2005 Apr;35(8):737-46. Loeffler J, Steffens M, Arlt EM, Toliat MR, Mezger M, Suk A, Wienker TF, Hebart H, Nurnberg P, Boeckh M, Ljungman P, Trenschel R, Einsele H. Polymorphisms in the genes encoding chemokine receptor 5, interleukin-10, and monocyte chemoattractant protein 1 contribute to cytomegalovirus reactivation and disease after allogeneic stem cell transplantation. J Clin Microbiol. 2006 May;44(5):1847-50. M. Hartmann, J. Brust, D. Schuster, F. Mosthaf, M. Procaccianti, J. A. Rump, H. Klinker, D. Petzold (2005). Arzneimittelexantheme bei Therapie der HIV-Infektion mit Efavirenz und Nevirapin. Hautarzt 56: 847-853 M. Hartmann, S. Witte, J. Brust, D. Schuster, F. Mosthaf, M. Procaccianti, A. Rump, H. Klinker, D. Petzoldt (2005). Comparison of Efavirenz and Nevirapine in HIV-infected patients (NEEF Cohort). Int J STD & AIDS 16: 404-409 Mandle T, Einsele H, Schaller M, Neumann D, Vogel W, Autenrieth IB, Kempf VA. Infection of human CD34+ progenitor cells with Bartonella henselae results in intraerythrocytic presence of B. henselae. Blood. 2005 Aug 15;106(4):1215-22. Mandle T, Einsele H, Schaller M, Neumann D, Vogel W, Autenrieth IB, Kempf VA. Infection of human CD34+ progenitor cells with Bartonella henselae results in intraerythrocytic presence of B. henselae. Blood. 2005 Aug 15;106(4):1215-22 Martino R, Bretagne S, Einsele H, Maertens J, Ullmann AJ, Parody R, Schumacher U, Pautas C, Theunissen K, Schindel C, Munoz C, Margall N, Cordonnier C; Infectious Disease Working Party of the European Group for Blood and Marrow Transplantation. Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation. Clin Infect Dis. 2005 Jan 1;40(1):67-78. Martino R, Parody R, Fukuda T, Maertens J, Theunissen K, Ho A, Mufti GJ, Kroger N, Zander AR, Heim D, Paluszewska M, Selleslag D, Steinerova K, Ljungman P, Cesaro S, Nihtinen A, Cordonnier C, Vazquez L, Lopez-Duarte M, Lopez J, Cabrera R, Rovira M, Neuburger S, Cornely O, Hunter AE, Marr KA, Dornbusch HJ, Einsele H. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2006 Nov 1;108(9):2928-36.

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N. Venhoff, M. Zilly, D. Lebrecht, D. Schirmer, H. Klinker, J. Thoden, P. Langmann, U. Walker (2005). Uridine pharmacokinetics of mitocnol, a sugar cane Extract. AIDS 19: 739-740 P Ljungman, A Urbano-Ispizua, M Cavazzana-Calvo, T Demirer, G Dini, H Einsele, A Gratwohl, A Madrigal, D Niederwieser, J Passweg, V Rocha, R Saccardi, H Schouten, N Schmitz, G Socie,A Sureda, and J Apperley for the European Group for Blood and Marrow Transplantation. Allogeneic and autologous transplantation for haematological diseases, solidtumours and immune disorders: definitions and current practice in Europe. Bone Marrow Transplant. 2006 Mar;37(5):439-49. P. Langmann, A. Trein, M. Zilly, H. Klinker, E. Schnaitmann (2005). Safety of lopinavir through plasmalevels in combination with NNRTI in a nuke free regimen. Eur J Med Res 10: 78-79 P. Langmann, D. Schirmer, H. Klinker (2006). Therapeutisches Dtrug Monitoring von Ribavirin – ein Parameter zur Individualisierung der HCV-Therapie. Med Klin 101: 104 P. Langmann, H. Klinker (2005). Koinfektion HIV und Hepatitis C. In: H. Jäger(Hrsg.): AIDS und HIV-Infektionen. Handbuch und Atlas für Klinik und Praxis. Ecomed Verlagsgesellschaft 1987ff (2005), V- 3.1.2, S. 1-14 P. Langmann, H. Klinker (2006). Pharmakologie und Therapeutisches Drug Monitoring.In: J. R. Bogner (Hrsg): Proteasehemmer in der HIV-Therapie, UNI-MED-Verlag Bremen London Boston, S. 89-98 P. Langmann, L. Schneider, M. Zilly, R. Winzer, H. Klinker (2005). Boosted double PI therapy in a patient with liver cirrhosis and NRTI-induced lactic acidosis. Eur J Med Res 10: 103 P. Langmann, M. Zilly, A. Katsounas, R. Winzer, A. Emmert, A. Knipper, H. Klinker (2005). Efavirenz long term therapy: no change of EFV levels. Eur J Med Res 10: 79 P. Langmann, M. Zilly, C. Hubert, R. Winzer, A. Emmert, H. Klinker (2005). Liver enzyme elevation in a LPV/r based therapy i soften only slight and mainly caused by GGT. Eur J Med Res 10: 79 P. Langmann, M. Zilly, R. Winzer, H. Klinker (2006). Therapeutic Drug Monitoring: A Tool to Individualize Highly Active Antiretroviral Therapy in HIV Infected Patients. Current Pharmaceutical Analysis 2: 205-217 Penack O, Beinert T, Buchheidt D, Einsele H, Hebart H, Kiehl MG, Massenkeil G, Schiel X, Schleicher J, Staber PB, Wilhelm S, Wolf HH, Ostermann H; German Society of Hematology and Oncology. Management of sepsis in neutropenia: guidelines of the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO).Ann Hematol. 2006 Jul;85(7):424-33 R. Eckert, M. Zilly, D. Schirmer, R. Winzer, H. Klinker, P. Langmann (2005). Uridine plasma levels of HIV-1 positive patients under antiretroviral therapy. Eur J Med Res 10: 111 R. Seggewiß, W. Heinz, V. Kunzmann, H. Klinker, H. Einsele (2006). Progressive multifocal leukencephalopathy after allogenic stem cell transplantation in multiple myeloma. Onkologie 29 (Suppl 3): 185-186 R. Winzer, P. Langmann, M. Zilly, D. Schirmer, B. Weissbrich, H. Klinker (2005). Interpretation of untimed lopinavir (LPV) drug levels – use in clinical practice. Eur J Med Res 10: 116 R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weissbrich (2005). No influence of the P-glycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naive HIV- positive patients. Annals of Clinical Microbiology and Antimicrobials (online) 4(1):3 R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weißbrich (2005). Kein Einfluss des P-Glykoprotein- Genotyps (MDR1 C3435T) auf die virologische und immunologische Response therapienaiver HIV-Patienten. Med. Klinik 100: 91 R. Winzer, P. Langmann, M. Zilly, F. Tollmann, J. Schubert, H. Klinker, B. Weissbrich (2005). No influence of the P-glycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naïve HIV- positive patients. Eur J Med Res 10: 78 Reich G, Cornely OA, Sandherr M, Kubin T, Krause S, Einsele H, Thiel E, Bellaire T, Dörken and Maschmeyer G. Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial. Br J of Haematol 2005 (130):265-270 S.E. Eckert, W. J. Heinz, K. Zakikhany, S. Thewes, K. Haynes, B. Hube, F. A. Mühlschlegel (2006). PGA4, a GAS homologue from Candida albicans, is up-regulated early in infection processes. Fungal Genet Biol, in press Sandherr M, Einsele H, Hebart H, Kahl C, Kern W, Kiehl M, Massenkeil G, Penack O, Schiel X, Schuettrumpf S, Ullmann AJ, Cornely OA; Infectious Diseases Working Party, German Society for Hematology and Oncology. Antiviral prophylaxis in patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO).Ann Oncol. 2006 Jul;17(7):1051-9 Stuhler G, Knop S, Topp MS, Krober SM, Ernemann U, Herrlinger U, Einsele H, Kanz L, Hebart H. Intravenously administered rituximab induces remission of EBV associated non Hodgkin lymphoma confined to the brain in a patient after allogeneic stem cell transplantation. Haematologica. 2006 Mar;91(3):ECR01. T. Berg, M. von Wagner, H. Hinrichsen, C. Sarrazin, T. Heintges, T. Gerlach, P. Buggisch, T. Goeser, J. Rasenack, G. Pape, W. E. Schmidt, B. Kallinowski, H. Klinker, U. Spengeler, P. Martus, U. Alshuth, S. Zeuzem (2006). Extended Treatment

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Duration for Hepatitis C Virus Type 1: A Randomized Trial Comparing 48 versus 72 Weeks of Peginterferon-alfa-2a plus Ribavirin.Gastroenterology 130: 1086-1097 T. Berg, V. Weich, G. Teuber, H. Klinker, B. Möller, J. rasenack, H. Hinrichsen, G. Pape, U. Spengler, P. Buggisch, M. Zankel, H.Balk, C. Sarrazin, S. Zeuzem (2006). Individualisierte Therapiestrategie mit Peginterferon alfa-2b (PEG-IFNa) plus Ribavirin in Abhängigkeit von der frühen Viruskinetik bei Hepatitis C Virus (HCV) Typ 1-infizierten Patienten. Z Gastroenterol 44: 130 T. Weitzel , N. Muhlberger, T. Jelinek, M. Schunk, S. Ehrhardt, C. Bogdan, K. Arasteh, T. Schneider, W. Kern, G. Fatkenheuer, G. Boecken, T. Zoller, M. Probst, M. Peters T. Weinke, S. Gfrorer, H. Klinker, M. Holthoff-Stich (2005). Surveillance Importierter Infektionen in Deutschland (SIMPID) Surveillance Network. Imported leishmaniasis in Germany 2001- 2004: data of the SIMPID surveillance network. Eur J Clin Microbiol Infect Dis. 24: 471-476 V. Weich, G. Teuber, C. Sarrazin, H. Klinker, P. Buggisch, E. Schott, A. Bergk, H. Witt, T. Berg (2006). Einfluss des Apolipoprotein E4 Allels auf das Therapieansprechen mit PEG-IFNa plus Ribavirin mit Hepatitis C Virus (HCV)-Typ 1-Infektion. Z Gastroenterol 44: 126 Vogel W, Kopp HG, Kanz L, Einsele H.Myeloma cell contamination of peripheral blood stem-cell grafts can predict the outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation.J Cancer Res Clin Oncol. 2005 Apr;131(4):214-8. W. Heinz, C. Klöser, C. Guhl, A. Helle, H. Einsele, H. Klinker (2006). Surveillance of voriconazole plasma concentrations in patients with haematological malignancies. Onkologie 29 (Suppl 3): 216-217

3-9 Institute of Neurology, (in the field of Immunology and Infectiology):

Perron H,, Lazarini F, Ruprecht K, Péhoux-Longin C, Seilhean D, Sazdovitch V, Cr•ange A, Battail-Poirot N, Sibai G, Santoro L, Jolivet M, Darlix JL, Rieckmann P, Arzberger T, Hauw JJ, Lassmann H. (2005) Human endogenous retrovirus (HERV)-W env and gag proteins: physiological expression in human brain and physiopathological modulation in multiple sclerosis lesions. J. Neurovirol. 11: 23-33. Kroner A, Rosche B, Kolb-Mäurer A, Kruse N, Toyka KV, Hemmer B, Rieckmann P, MŠurer M. (2005) Impact of the Asp299Gly polymorphism in the toll-like receptor 4 (tlr-4) gene on disease course of multiple sclerosis. J. Neuroimmunol. 165: 161- 5. Ruprecht K, Obojes K, Wengel V, Gronen F, Kim KS, Perron H, Schneider-Schaulies J, Rieckmann P.(2006) Regulation of human endogenous retrovirus-W protein expression by herpes simplex virus type 1: Implications for the pathogenesis of multiple sclerosis. J. Neurovirol. 12; 65-72. Buttmann M, Berberich-Siebelt F, Serfling E, Rieckmann P. (2007) Interferon-b Is a Potent Inducer of STAT1/2-mediated MCP-1/ CCL2 and of IRF-1/2-dependent IP-10/CXCL10 Chemokine Expression in Primary Human Endothelial Cells J. Vasc. Res. 44: 51-60. Gronen F, Ruprecht K, Weissbrich B, Klinker E, Hofstetter H, Kroner A, Rieckmann P. (2006)Frequency of HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis. J. Neuroimmunol. 180: 185-192

3-10 Children Hospital - Pedriatic Infectiology, (in the field of Immunology and Infectiology):

D’Alquen, D., Kramer, B.W., Seidenspinner, S., Marx, A., Berg, D., Groneck, P., Speer, C.P. (2005) Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res 57: 263-269 Girschick, H.J., Raab, P., Surbaum, S., Trusen, A., Kirschner, S., Schneider, P., Papadopoulos, T., Muller-Hermelink, H.K., Lipsky, P.E. (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64: 279-285. Klotz, P., Tappe, D., Abele-Horn, M., Warmuth-Metz, M., Sorensen, N., Speer, C.P., Girschick, H.J. (2006) Cerebral mass in a 13- year-old girl following long-term sojourn in the Tropics. J Med Microbiol 55: 345-347. Kramer, B.W., Kaemmerer, U., Kapp, M., Herbst, D., Marx, A., Berg, D., Groneck, P.A., Speer, C,P. (2005) Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr Res 58(3):607-612 Koenig, C., Hebestreit, H., Valenza, G., Abele-Horn, M., Speer, C.P. (2005) Legionella waltersii – a novel cause of pneumonia? Acta Paediatr 94:1505-7 Kunzmann, S., Warmuth-Metz, M., Girschick, H.J. (2005) Cerebral demyelination in association with TNF-inhibition therapy in a 5-year-old girl with aseptic meningitis as the first symptom of Still’s disease. Scand J Rheumatol 34: 76-78. Kunzmann, S., Speer, C.P., Jobe, A.H., Kramer, B.W. (2006) Antenatal inflammation induced TGF-â1 but suppressed CTGF in preterm lungs. Am J Physiol Lung Cell Mol Physiol, in press Kunzmann, S., Wright, J.R., Steinhilber, W., Kramer, B.W., Blaser, K., Speer, C.P., Schmidt-Weber, C. (2006) TGF-â1 in SP-A

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preparations influences immune suppressive properties of SP-A on human CD4+ T lymphocytes. Am J Physiol Lung Cell Mol Physiol, in press Maschmann, J., Hamprecht, K., Weissbrich, B., Dietz, K., Jahn, G., Speer, C.P. (2006) Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal Ed 91:F288-90 Neuberger, P., Hamprecht, K., Vochem, M., Maschmann, J., Speer, C.P., Poets, C.F., Goelz, R. (2006) Case control study of symptoms and neonatal outcome of human milk-transmitted cytomegalovirus infection in preterm infants. J Pediatr 148(3):326-31 Siauw, C., Kobsar, A., Dornieden, C., Beyrich, C., Schinke, B., Schubert-Unkmeir, A., Abele-Horn, M., Speer, C.P., Eigenthaler, M. (2006) Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signalling cascades. Thrombosis and Haemostasis 95(5):836-49 Singh, S.K., Girschick, H.J. (2004a) Molecular survival strategies of the Lyme disease spirochete Borrelia burgdorferi. Lancet Infect Dis 4: 575-583. Singh, S.K., Girschick, H.J. (2004b) Lyme borreliosis: from infection to autoimmunity. Clin Microbiol Infect 10: 598-614. Singh, S.K., Morbach, H., Nanki, T., Faber, C., Baar, V., Girschick, H.J. (2004) Differential expression of matrix metalloproteinases and cyclooxygenases in synovial cells exposed to Borrelia burgdorferi. Inflamm Res 53: 689-696. Singh, S.K., Morbach, H., Nanki, T., Girschick, H.J. (2005) Differential expression of chemokines in synovial cells exposed to different Borrelia burgdorferi isolates. Clin Exp Rheumatol 23: 311-322. Singh, S.K., Baar, V., Morbach, H., Girschick, H.J. (2006) Expression of ICAM-1, ICAM-2, NCAM-1 and VCAM-1 by human synovial cells exposed to Borrelia burgdorferi in vitro. Rheumatol Int 26: 818-827. Singh, S.K., Girschick, H.J. (2006) Toll-like receptors in Borrelia burgdorferi-induced inflammation. Clin Microbiol Infect 12: 705-717. Sitaru, A.G., Holzhauer, S., Speer, C.P., Singer, D., Obergfell, A., Walter, U., Speer, C.P., Grossmann, R. (2005) Neonatal platelets: Are they different? Platelets 16:203-210 Sitaru, A.G., Speer, C.P., Holzhauer, S., Obergfell, A., Walter, U., Grossmann, R. (2005) Chorioamnionitis is associated with increased CD40L expression on cord blood platelets. Thromb Haemost 94(6):1219-23 Speer, C.P. (2006) Pulmonary inflammation and bronchopulmonary dysplasia. J Perinatol 26(1):S57-62. Speer, C.P. (2006) Inflammation and Bronchopulmonary Dysplasia: A Continuing Story. Sem Fetal Neonat Med 11(5):354-62. Thomas, W., Speer, C.P. (2005) Best practice guidelines: Management of infants with bronchopulmonary dysplasia in Germany. Early Human Development 81(2): 155-163 Valenza, G., Burgemeister, S., Girschick, H., Schoen, C., Veihelmann, S., Moter, A., Haban, V., Vogel, U., Schlagenhauf, U. (2006) Analysis of the periodontal microbiota in childhood-type hypophosphatasia. Int J Med Microbiol.Nov;296(7):493- 500.

3-11 Department of Skin Diseases and Veneral Diseases (in the field of Immunology and Infectiology):

Andersen MH, Becker JC, Straten P. Regulators of apoptosis: suitable targets for immune therapy of cancer. Nat Rev Drug Discov. 2005 May;4:399-409. Andersen MH, Reker S, Kvistborg P, Becker JC, thor Straten P. Spontaneous immunity against Bcl-xL in cancer patients. J Immunol. 2005 Aug 15;175:2709-14. Becker JC, Houben R, Vetter CS, Broecker EB. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report. BMC Cancer.Jan 2006; 11;6:7 Friedl P, den Boer AT, Gunzer M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat Rev Immunol. 2005 Jul;5:532-45. Gesierich A, Herzog S, Grunewald SM, Tappe D, Bröcker EB, Schön MP: Eosinophilic folliculitis in a Caucasian patient: Association with toxocariasis? J. Eur. Acad. Dermatol. 20, 1317-1321, 2006 Hamm H. Mites, lice and fleas. Ectoparasitoses in infancy and childhood. Hautarzt. 2005 Oct;56:915-24. Herrero-Gonzalez JE, Sitaru C, Klinker E, Brocker EB, Zillikens D. Successful adjuvant treatment of severe bullous pemphigoid by tryptophan immunoadsorption. Clin Exp Dermatol. 2005 Sep;30:519-22. Hofmeister V, Vetter C, Schrama D, Brocker EB, Becker JC. Tumor stroma-associated antigens for anti-cancer immunotherapy. Cancer Immunol Immunother. 2005 Oct 12:1-14 Hofmeister V, Vetter C, Schrama D, Brocker EB, Becker JC. Tumor stroma-associated antigens for anti-cancer immunotherapy. Cancer Immunol Immunother. 2005 Oct 12:1-14 Kerstan A, Rose C, Simon D, Simon HU, Brocker EB, Trautmann A, Leverkus M. Bullous delayed pressure urticaria: pathogenic role for eosinophilic granulocytes? Br J Dermatol. 2005 Aug;153:435-9. Kerstan A, Schön MP: Viewpoint: Who is really in control of skin immunity under physiological circumstances -–lymphocytes, dendritic cells, or keratinocytes? Exp. Dermatol.15, 929, 2006

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Kroner A, Vogel F, Kolb-Maurer A, Kruse N, Toyka KV, Hemmer B, Rieckmann P, Maurer M. Impact of the Asp299Gly polymorphism in the toll-like receptor 4 (tlr-4) gene on disease course of multiple sclerosis. J Neuroimmunol. 2005 Aug;165:161-5. Kurzai O, Schmitt C, Brocker E, Frosch M, Kolb-Maurer A. Polymorphism of Candida albicans is a major factor in the interaction with human dendritic cells. Int J Med Microbiol. 2005 Jun;295:121-7 Kurzai O, Schmitt C, Claus H, Vogel U, Frosch M, Kolb-Maurer A. Carbohydrate composition of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell Microbiol. 2005 Sep;7:1319-34. Ludwig RJ, Zollner TM, Santoso S, Hardt K, Gille J, Baatz H, Johann PS, Pfeffer J, Radeke HH, Schon MP, Kaufmann R, Boehncke WH, Podda M. Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation. J Invest Dermatol. 2005 Nov;125:969-76. Ludwig RJ, Zollner TM, Santoso S, Hardt K, Gille J, Baatz H, Schulze Johann P, Pfeffer J, Radeke HH, Schön MP, Kaufmann R, Boehncke WH, Podda M: Junctional adhesion molecules (JAM)-B and –C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation. J. Invest. Dermatol. 125, 969-976, 2005 Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LO, Rath JC, Bock M, Brocker EB, Straten PT, Kampgen E, Becker JC. Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine. 2005 Jan 4;23:884-9. Rose E, Wever S, Zilliken D, Linse R, Haustein UF, Brocker EB. Intravenous examethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter prospectively randomized study. J Dtsch Dermatol Ges. 2005 Mar;3:200-6. Schad SG, Trcka J, Vieths S, Scheurer S, Conti A, Brocker EB, Trautmann A. Wine Anaphylaxis in a German Patient: IgE- Mediated Allergy against a Lipid Transfer Protein of Grapes. Int Arch Allergy Immunol. 2005 Jan 12;136:159-164 Schmid-Grendelmeier P, Fluckiger S, Disch R, Trautmann A, Wuthrich B, Blaser K, Scheynius A, Crameri R. IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin Immunol. 2005 May;115:1068-75. Schoen C, Kolb-Maurer A, Geginat G, Loffler D, Bergmann B, Stritzker J, Szalay AA, Pilgrim S, Goebel W. Bacterial delivery of functional messenger RNA to mammalian cells. Cell Microbiol. 2005 May;7:709-24. Schön MP, Boehncke WH, Bröcker EB: Psoriasis – clinical manifestations, pathogenesis and therapeutic perspectives. Discovery Medicine 5, 253-258, 2005 Schön MP, Boehncke WH: Psoriasis. N. Engl. J. Med. 352, 1899-1912, 2005 Schon MP, Ludwig RJ. Lymphocyte trafficking to inflamed skin—molecular mechanisms and implications for therapeutic target molecules. Expert Opin Ther Targets. 2005 Apr;9:225-43. Schön MP, Schön M, Klotz KN: The small anti-tumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and 8-independent fashion. J. Invest. Dermatol. 126, 1338-1347, 2006 Schön MP, Schön M: The small-molecule immune response modifier imiquimod – Its mode of action and clinical use in the treatment of skin cancer. Expert Opin. Ther. Targets 10; 69-76, 2006 Schön MP: Advances in psoriasis treatment. Lancet 366, 1333-1335, 2005 Schön MP: Inhibitors of selectin functions in the treatment of inflammatory skin disorders. Therapeutics Clin. Risk. Management, 1, 201-208, 2005 Schön MP: Leukocyte extravasation as a target for anti-inflammatory therapy – which molecule to choose? Exp. Dermatol. 14, 74-76, 2005 Schrama D, Terheyden P, Otto K, Kammerer U, Brocker EB, Luhder F, Cosman D, Andersen MH, Becker JC. Expression of the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cells. Eur J Immunol. Jan 2006;36:65-72 Schubert B, Grosse Perdekamp MT, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Nonsteroidal anti-inflammatory drug hypersensitivity: fable or reality? Eur J Dermatol. 2005 May-Jun;15:164-7. Siegmund D, Wicovsky A, Schmitz I, Schulze-Osthoff K, Kreuz S, Leverkus M, Dittrich-Breiholz O, Kracht M, Wajant H. Death receptor-induced signaling pathways are differentially regulated by gamma interferon upstream of caspase 8 processing. Mol Cell Biol. 2005 Aug;25:6363-79. Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, Krenn V, Schön MP, Scheffold A, Lowe JB, Hamann A, Syrbe U, Huehn J: Migration matters: regulatory T cell compartmentalization determines suppressive activity in vivo. Blood 106, 3097-3104, Nov 2005 Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, Krenn V, Schön MP, Scheffold A, Lowe JB, Hamann A, Syrbe U, Huehn J: Migration matters: regulatory T cell compartmentalization determines suppressive activity in vivo. Blood 106, 3097-3104, 2005 Straten PT, Dahl C, Schrama D, Pedersen LO, Andersen MH, Seremet T, Brocker EB, Guldberg P, Becker JC. Identification of identical TCRs in primary melanoma lesions and tumor free corresponding sentinel lymph nodes. Cancer Immunol Immunother. 2005 Jul 7:1-8

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Trautmann A, Kruger K, Akdis M, Muller-Wening D, Akkaya A, Brocker EB, Blaser K, Akdis CA. Apoptosis and loss of adhesion of bronchial epithelial cells in asthma. Int Arch Allergy Immunol. 2005 Oct;138(2):142-50 Trujillo-Vargas CM, Ramirez-Pineda JR, Palmetshofer A, Grunewald S, Moll H, Berberich C, Erb KJ. Mice vaccinated with allergen-pulsed myeloid dendritic cells are not protected from developing allergen-induced Th2 responses. Int Arch Allergy Immunol. 2005 Jul;137:219-28. Vassina E, Leverkus M, Yousefi S, Braathen LR, Simon HU, Simon D. Increased expression and a potential anti-inflammatory role of TRAIL in atopic dermatitis. J Invest Dermatol. 2005 Oct;125:746-52. Voigt H, Schrama D, Eggert AO, Vetter CS, Muller-Blech K, Reichardt HM, Andersen MH, Becker JC, Luhder F. CD28- mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol. 2006 Jan;143:93-102. Voigt H, Schrama D, Eggert AO, Vetter CS, Muller-Blech K, Reichardt HM, Andersen MH, Becker JC, Luhder F. CD28- mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol. 2006 Jan;143:93-102. Waschke J, Bruggeman P, Baumgartner W, Zillikens D, Drenckhahn D. Pemphigus foliaceus IgG causes dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction. J Clin Invest. 2005 Nov;115:3157- 65. Weyandt GH, Benoit S, Becker JC, Brocker EB, Hamm H. Controlled layered removal of anogenital warts by argon-plasma coagulation. J Dtsch Dermatol Ges. 2005 Apr;3:271-5. Wienrich BG, Krahn T, Schön M, Rodriguez ML, Kramer B, Busemann M, Boehncke WH, Schön MP: Structure-function relation of efomycines, a family of small-molecule inhibitors of selectin functions. J. Invest. Dermatol. 126, 882-889, 2006. 3-12 Surgical Clinic with Out-patients' Department (in the field of Infectiology):

Lorenz, U; Ohlsen, K; Karch, H; Hecker, M; Thiede, A; Hacker, J. Human antibody response during sepsis against targets expressed by methicillin resistant Staphylococcus aureus. FEMS Immunol Med Microbiol 2000 29(2):145-53. Lorenz, U; Ohlsen, K; Karch, H; Thiede, A; Hacker, J. Immunodominant proteins in human sepsis caused by methicillin resistant Staphylococcus aureus. Adv Exp Med Biol 2000;485:273-8. Lorenz, U; Hüttinger, C; Ziebuhr, W; Würzler, C; Thiede, A; Hacker, J; and Ohlsen, K. The alternative sigma factor sigma B of Staphylococcus aureus is crucial for the development of infection in a clinical model of sepsis Infection and Immunity, 2007, submitted Lorenz U, Hüttinger C, Wehland J, Werner B, Schäfer T, Thiede A, Hacker J and Ohlsen K. Therapeutic activity of a novel monoclonal antibody (MAB-ISAA29) against Staphylococcus aureus J Exp Med 2007, submitted

3-13 Department of Tropical Medicine at the Medicinical Misso Hospital:

Abdel-Aziz, I.Z., Oster, N., Stich, A., Coulibaly, B., Guigemde, W.A., Wickert, H., Andrews, K.T., Kouyate, B., and Lanzer, M. (2005) Association of Plasmodium falciparum isolates encoding the p. Falciparum chloroquine resistance transporter gene K76T polymorphism with anemia and splenomegaly, but not with multiple infections. Am J Trop Med Hyg 72: 252-255. Agranoff, D., Stich, A., Abel, P., and Krishna, S. (2005) Proteomic fingerprinting for the diagnosis of human African trypanosomiasis. Trends Parasitol 21: 154-157. Inojosa, W.O., Augusto, I., Bisoffi, Z., Josenado, T., Abel, P.M., Stich, A., and Whitty, C.J. (2006) Diagnosing human African trypanosomiasis in Angola using a card agglutination test: observational study of active and passive case finding strategies. Bmj 332: 1479. Oster, N., Abdel-Aziz, I.Z., Stich, A., Coulibaly, B., Kouyate, B., Andrews, K.T., McLean, J.E., and Lanzer, M. (2005) Comparison of different PCR protocols for the detection and diagnosis of Plasmodium falciparum. Parasitol Res 97: 424-428. Schmidt, E., Weissbrich, B., Brocker, E.B., Fleischer, K., Goebeler, M., and Stich, A. (2006) Orf followed by erythema multiforme. J Eur Acad Dermatol Venereol 20: 612-613. Stich, A., Oster, N., Abdel-Aziz, I.Z., Stieglbauer, G., Coulibaly, B., Wickert, H., McLean, J., Kouyate, B.A., Becher, H., and Lanzer, M. (2006) Malaria in a holoendemic area of Burkina Faso: a cross-sectional study. Parasitol Res 98: 596-599. Tappe, D., Winzer, R., Buttner, D.W., Strobel, P., Stich, A., Klinker, H., and Frosch, M. (2006) Linguatuliasis in Germany. Emerg Infect Dis 12: 1034-1036. Vicik, R., Hoerr, V., Glaser, M., Schultheis, M., Hansell, E., McKerrow, J.H., Holzgrabe, U., Caffrey, C.R., Ponte-Sucre, A., Moll, H., Stich, A., and Schirmeister, T. (2006) Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypa- nosoma brucei as lead trypanocidal agents. Bioorg Med Chem Lett 16: 2753-2757. Weinke, T., Liebold, I., Burchard, G.D., Fruhwein, N., Grobusch, M.P., Hatz, C., Kollaritsch, H., Nothdurft, H.D., Reisinger, E., Rieke, B., Schonfeld, C., Steffen, R., and Stich, A. (2006) [Prophylactic immunization against enterotoxin-forming Escherichia coli travellers’ diarrhea and cholera: does it make sense and for whom?]. Dtsch Med Wochenschr 131: 1660-1664.

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