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ERA-NET PathoGenoMics

Produced by CSO-MOH, Israel Grant number: ERAC-CT-2044-006973

Produced by Produced by CSO-MOH, Israel CSO-MOH, Israel 1 |

Foreword Zsuzsanna Kőnig, Project Officer I have been a project officer for the PathoGeMonics ERA-NET since 2008, and I always appreciated its smooth and efficient work. In its long life of 8 years, it has managed to form a strong, open minded and creative network of public funding agencies in Europe and to establish effective co-ordination of national research programmes in human pathogenic microorganisms. PathoGenoMics has performed very well in establishing a common ground for launching regular joint calls and PhD awards. It has also established a solid monitoring system of the funded research projects. It has excelled in strong science for society activities as well as in innovation related actions. A very positive spill-over of the best practices from PathoGenoMics to the ERA-NET community has taken place. I believe that it is very important to have such efficient communities of public research funders in Europe to find solutions for long-standing or emerging problems such as diseases caused by and fungi. They can contribute to reducing duplication in European research funding, to increasing synergies among Member States as well as to forming joint strategies. I would like to congratulate the PathoGenoMics network for their valuable work and excellent results. |2 3 |

Foreword Executive Summary: Giorgio Clarotti ERA-NET PathoGenoMics, a project funded by the European Commission launched in PATHOGENOMICS: I REMEMBER THAT... September 2004 was established to coordinate -based research programmes on I remember joining the ERA coordination unit in spring 2005. The objective was to allow human-pathogenic microorganisms and to consolidate cooperation between the national programme managers to work together. In some countries there were no such figures, so agencies funding this research in the participating countries. involving ministries, which we called programme owners, became the first challenge. The funding institutions from partner countries participating in ERA-NET PathoGenoMics I remember meeting the PathoGenoMics project in September 2005, in Helsinki. It was a include: glorious summer day and the city like it could be on a Mediterranean shore.  Austria- Federal Ministry for Science and Research (BMWF) and Austrian Science Fund We met in the splendid “Paasitorni” conference centre, which friendly warmth helped us (FWF); launch off fighting the super-bugs.  Finland-:Academy of Finland (AKA); The project had been going on for a year, but this was when it was decided to launch the  France- Institut Pasteur (IP), and The National Agency for Research (ANR); first joint call. The main discussion led to the decision, I remember that, to be inclusive:  Germany- Federal Ministry of Education and Research (BMBF) and Project Management addressing both bacterial and fungal of, again, both humans and animals. Juelich (PtJ); I recall having to leave “my” ERA-NETs to focus on the Joint Programming process. This  Hungary- Hungarian Academy of Science (HAS) and Hungarian Scientific Research Fund was a sad decision, but “my” ERA-NET sprouts had grown and it was time to move to (OTKA); something new.  Israel- The Chief Scientist Office, Ministry of Health (CSO-MOH); I remember sitting in the Council when the High Level group on Joint Programming (better  Portugal- The Science and Technology Foundation (FCT); known under its French acronym “GPC”) selected, after a hot discussion the launch of a Joint  Slovenia- Ministry of Higher Education, Science and Technology (MHEST); Programming Initiatives on the microbial resistance societal challenge. This was officially  Spain - Ministry of Science and Innovation (MICINN). launched by the ministers gathered in the Competitiveness Council of December 2011. Funding for ERA-NET PathoGenoMics activities started in September 2004 and ended in According to the first mapping, this area is one where European cooperation is the strongest. August 2012. A first mapping suggests that, together, FP7 and ERA-NET PathoGenoMics account for The transnational framework of ERA-Net PathoGenoMics significantly advanced some 50/60% of all research in microbial resistance in the European Research Area. pathogenomics research by providing the means to overcome obstacles imposed by The future challenge is, for me, that an adequate governance is developed to national research programmes, such as limitations on funding research and unnecessary ensure that activities in national and European programmes develop synergies and duplication of efforts. Within the course of the PathoGenoMics programme, a mapping of complementarities so that, together, they effectively address the “superbugs” we pathogenomic-related research programmes was carried out by surveying the activities of started fighting jointly in 2005. partners as well as those of funding organizations outside of Europe. A strategic research agenda in pathogenomics was articulated and published in 20081. In addition, a web portal on ERA-NET PathoGenoMics' innovative activities was constructed and two PathoGenoMics Innovation Partnership (PIP) workshops were held. The information gathered in these workshops as well as a comprehensive analysis of pathogenomics-related Research and Technological Development (RTD) was detailed in the PathoGenoMics Innovation Paper, published in 20082. The core and most important achievement of ERA-NET PathoGenoMics, however, was the launch of three Joint Transnational Calls (JTCs) for research projects. While the first call aimed primarily at strengthening basic research in the field of functional of human- and fungi, the second and third calls focused more heavily on application and consolidated cooperation between academia and the clinical and industrial participants.

1 | Demuth A, Aharonowitz Y, Bachmann T. , Blum-Oehler G, Buchrieser C, Covacci A, et al, ." Pathogenomics: an Updated European Research Agenda", Infection, Genetics and Evolution. 2008;8(3):386-93 2 | ERA-NET PathoGenoMics Innovation, Pathogenomics, Innovation and Public Health, http://www.pathogenomics-era.net/innovation/index.php?index=88 Giorgio Clarotti, former project officer, ERA-NET PathoGenoMics |4 5 |

These calls included topics pertaining to the prevention, diagnosis, treatment and monitoring What is ERA-NET? of infectious diseases, hence supported the transfer of the findings from basic research into The European Research Area Network (ERA-NET) is a European Commission initiative clinical and industrial applications. The number of funded scientists increased from the first launched within the Sixth and Seventh Framework Programmes, which is designed to to the second and third JTCs. The ERA-NET partners dedicated approximately €41.9 million to deepen scientific collaboration and coordination by facilitating transnational scientific fund projects approved under the three JTCs. Due to the high volume of applications received research. National and regional ministries and funding organisations comprise the in the first call, the application and selection process was revised for the subsequent calls, to ERA-NET partners. The main objective of an ERA-NET is to provide a framework to a two-step submission (pre-proposals and full proposals) evaluation process. promote networking by mutually opening national and regional research programmes to Project monitoring was conducted through a series of scientific and financial reports sent transnational research. ERA-NET programme sets the framework for concrete cooperation, by the coordinators. In addition, status seminars were held in which scientists presented such as the development and implementation of joint transnational calls. ERA-NET activity their work to the funding agencies and representatives of the programmes' Scientific complements EU research programmes, and the EU Commission funds both networking Advisory Board (SAB). activities and the management of the joint calls. Funding of the research activities resulting ERA-NET PathoGenoMics promoted the participation of young scientists in a number from the ERA-NET calls, however, is derived from the budgets of the regional and national of ways. Procedure was established to support consortia comprised and led by young ERA-NET partners. scientists. In addition, over the duration of the project, 17 doctoral students were awarded for exceptional doctoral theses in the field of pathogenomics. These were bestowed to the recipients at ceremonies held during major scientific conferences. Information regarding ERA-NET PathoGenoMics activities was disseminated by newsletters, flyers, brochures, press releases, help desks and the internet. An interactive teaching tool for junior high school students was also launched under the programme. "ERA-NET" is a Coordination Action (CA) scheme supported by the In preparation for follow-on activities, the overall efficiency and effectiveness of ERA- European Commission, designed to strengthen scientific foundations NET PathoGenoMics and its activities were evaluated by participating scientists and throughout Europe and to support the structure of the European agencies who were asked to fill a questionnaire on the programme's achievements and Research Area (ERA). Within this framework, ERA-Net PathoGenoMics on the future of concerted action in the study of infectious disease. The questionnaire was has created an cross-border venue for pathogenomics research, structured in three main sections: a) a general assessment of ERA-NET PathoGenoMics fostering information sharing and exchange of know-how, mobility of main achievements; b) assessment of concepts and tools for conducting transnational human resources, support of innovation and technology transfer. activities, including the implementation of transnational research and training activities; The ERA-NET PathoGenoMics network was initiated in 2004 with the and c) assessment of ancillary ERA-NET PathoGenoMics activities. The results of this objective of reducing fragmentation and duplication in pathogenomics survey showed that overall, the partners were very positive about the network. research, creating an "internal market" for pathogenomics by An application for future funding of a follow-on ERA-NET initiative, named Infect-ERA, was fostering transnational cooperation, an exchange of know-how, submitted to the Commission at the beginning of 2012 and has since been approved. "Infect- and mobility of human resources and by creating a transnational ERA" is designed to have a broader scope, and will include innovative research addressing framework for supporting innovation and technology transfer. ERA- the complex relation between microbe environments and their molecular infection NET PathoGenoMics incorporates the four modes of cooperation and strategies, while integrating new approaches and technologies such as , coordination proposed by the EU: systematic exchange of information and systems biology. The dialogue between the host and infectious microbes, including and best practices; strategic planning; implementation of joint activities micro-organism transmission, and the role of host susceptibility factors (age, chronic and/ and the conduct of transnational research. or autoimmune disease, genetic susceptibility, etc.) that contribute to heterogeneous responses to infection, treatment and prevention are incorporated in the Infect-ERA agenda. The first joint transnational call is scheduled for launch in the beginning of 2013. Summarizing the activities conducted over the past eight years by funding organizations from nine ERA-NET partner countries, this publication aims at reaching a broad audience of decision and policy makers, scientists, technology transfer agencies, industry and the general public. It includes an overview of the activities of ERA-NET PathoGenoMics since its establishment in September 2004, information on the three calls for joint multinational research (JTCs) held, details regarding the research projects conducted and a vision for the future sustainability of supporting multinational research in this area. |6 7 |

The Rationale Behind PathoGenoMics ERA-NET Structure infections are among the leading causes of morbidity and mortality in humans. In order to ensure continuity and optimise efficiency, the following administrative Accordingly, the majority of research in this field is connected to infectious agents, which pose a framework was established: risk to the well being of the public. The prevention and treatment of infectious diseases creates Network Steering Committee (NSC) an ever-increasing medical challenge. Apart from the emergence of new patho-variants, existing The Network Steering Committee (NSC) is the highest decision-making body of pathogens exhibit enhanced resistance to anti-infective drugs. In addition, the surge in global PathoGenoMics. The NSC comprises senior directors from the respective national funding population exchange and transportation amplifies and complicates the perils of contagion. organizations responsible for the implementation of programme activities. Decisions are In order to better understand the nature of the disease-causing agents, the study of made according to majority rule, with one vote allotted each participant country. pathogenomics attempts to utilize data in the most effective manner and apply the newly Executive Board (EB) gained knowledge to help treat and even prevent disease. Today, with the advent of functional The Executive Board (EB) consists of the Work Package coordinators and is responsible for genomics we are able to rationally and systematically unravel pathogenesis-related genes, the planning, execution, coordination, monitoring and reporting of Work Package activities. thereby identifying new targets for diagnostics, therapeutics, and prevention. The EB meets quarterly in order to discuss the project’s progress and report to the NSC. Basic research in this field is a key element in the endeavour to comprehensively address the External Advisory Board (EAB) challenges to personal and public health posed by infectious disease. The findings uncovered The External Advisory Board (EAB) comprises high-level experts (two per partner by basic research promote the development of drugs, diagnostic tools and vaccines, which are country) from leading public research institutes, the biotechnological and pharmaceutical more highly attuned to the needs of individual patients and to the challenges presented by a industries as well as experts on legal and regulatory issues. The NSC consults with the EAB particular disease. A better understanding of pathogen generation and behaviour can expedite regarding various aspects of the project, since NSC and EB members are administrative and enhance clinical research towards the development of tools to improve the diagnosis, representatives and are not necessarily expert in the relevant fields. treatment, control and prevention of both the inception and spread of disease. Coordinator In contrast to human or plant genome research, which benefited from long lasting and well- The overall task of the coordinator is to ensure the implementation and progress of the ERA- coordinated national programmes in several European countries, the genome research on NET. The coordinator is the ERA-NET's representative and its focal contact person vis-a-vis human pathogenic microorganisms (termed as "pathogenomics") suffered from fragmentation the Commission, the partners of the network, the research community, and other networks. and lack of transparency. To overcome these problems, ERA-NET PathoGenoMics proposed The Coordinator interacts regularly with the national and regional funding agencies, the to structure intensive transnational research and innovation activities. ERA-NET provided relevant national contact persons and the individual research project coordinators and is a framework for a more efficient use of the resources allocated to this field by bundling and responsible for monitoring the overall budget of the ERA-NET and the work packages. In strategically focusing previously scattered funding, by stimulating mutual specializations of addition, the Coordinator represents the ERA-NET in European and international meetings. national research landscapes to enhance synergy, and by identifying and consequently avoiding The first ERA-NET PathoGenoMics coordinator was Dr. Rudolf Straub from the BMBF, duplications in research. As a result, a critical mass was created to embark on riskier, but highly followed by Dr. Marion Karrasch from Project Management Juelich (PtJ). Dr. Karrasch was innovative approaches that can enhance Europe's global competitiveness in this field. Through succeeded by Dr. Bülent Genç from the same organization in the beginning of 2011. structuring and promoting pathogenomics, a field of research which is economically important and often crucial from the standpoint of public health, a more stimulating and encouraging environment for innovation has been created. The closer cooperation with clinical and industrial organizations attained through ERA-NET holds the promise of more effective commercial exploitation of the research findings, primarily by small and medium enterprises (SMEs). |8 9 |

ERA-NET PathoGenoMics Work Packages KEY ERA-NET Activities (WPs): (WPs): WP 1: Status Quo of the Partner Countries’

WP No: Content Lead by Programmes/programme areas

1 Status Quo of the Partner Countries’ Germany, Federal Ministry of WP 2: Strengthening the Knowledge Base Programmes/programme Areas Education and Research (BMBF) and Project Management Juelich (PtJ) for Long-term RTD Strategies Hungary, Hungarian Academy of Science (HAS) and Hungarian WP Leader: Germany, Federal Ministry of Education and Research (BMBF) and Project Scientific Research Fund (OTKA) Management Juelich (PTJ) Hungary, Hungarian Academy of Science (HAS) and Hungarian Scientific Research Fund 2 Strengthening the Knowledge Base Germany, Federal Ministry of (OTKA) for Long-term (RTD) Strategies Education and Research (BMBF) and Project Management Juelich (PtJ) The ERA-NET era dates back to 2004. At the time of the programme's inception, multinational collaboration between the national organizations funding scientific research 3 Strategic and Analytical Activities France, Institut Pasteur (IP) was neither as accepted or understood as it is today. It was imperative, therefore, that prior to launch the first joint call for research projects, the groundwork for transnational 4 Economic Exploitation and Job France, Institut Pasteur (IP) collaboration be prepared. Towards this end, one of the first priorities was to study the Creation current status of pathogenomics research in each of the partner countries. This included 5 Support for Transnational Finland, Academy of Finland (AKA) surveying administrative procedures and the legal infrastructure, as well as the fields of Consortium Building pathogenomics research undertaken, in each country. The first two ERA-NET PathoGenoMics work packages were dedicated to mapping the 6 Human Resources Development and Austria, Federal Ministry for Science Mobility and Research (BMWF) status quo of pathogenomics-related research in the partner countries and programme areas. This was achieved through collaboration between all EB members. 7 Management Concepts and Tools for Spain, Ministry of Science and In the initial part of the project, a survey was conducted of programme areas and existing Transnational Activities Innovation (MICINN) international cooperation schemes in partner and Third countries. This survey analyzed programme strategies and administrative procedures in the area of genome 8 Implementing Transnational Spain, Ministry of Science and Research and Training Innovation (MICINN) and functional genomics of human-pathogenic microorganisms in Europe and beyond (USA, China, Japan, Canada and Brazil, among others). In addition, in order to foster 9 Science to Society Israel, The Chief Scientist Office, collaboration in Europe, an interactive project database on projects and researchers in the Ministry of Health (CSO-MOH) field of genomics of human-pathogenic microorganisms was compiled1. While presenting the results of this mapping at the EB/NSC meeting held in Bonn, Germany 10 Consortium Management Germany, Federal Ministry of Education and Research (BMBF) and in April 2005, the partners were made aware of good practices instituted by various research Project Management Juelich (PtJ) funds, some of which were subsequently applied upon return to the home country. The collaboration practiced during the mapping process proved to be fertile ground for 11 Evaluation of ERA-NET Portugal, The Science and Technology important collaborations throughout the duration of the ERA-NET programme. PathoGenoMics Activities: Foundation (FCT) The Partners Perspective

1 | Interactive Information System on PathoGenoMics (IISP): www.pathogenomics-era. net/IISP/ |10 11 |

WP 3: Strategic and Analytical Activities WP leader: France, Institut Pasteur (IP) The purpose of this work package was to analyse the potential for synergy engendered in cooperation between the partner countries by identifying the opportunities, redundancies and gaps in the area of pathogenomics. This analysis led to the publication of the strategic agenda for pathogenomic-related research in Europe1. The initial strategic meeting for this work package was held in conjunction with the second NSC and third EB meeting at the Institit Pateur in Paris in May 2005. The meeting consisted of presentations of current research in the various countries as well as in-depth discussions. It was attended by high-level experts, who provided important feedback from the scientific community in European countries. Immediately following this session, a meeting on intellectual property rights was held, during which experts discussed the challenges of conducting multinational research and the means to address these challenges. During a subsequent meeting held in Villa Vigoni, Menaggio, Italy in April, 2007 a draft of the strategic research agenda was discussed and modified in collaboration with experts of the Network of Excellence (NoE) EuroPathoGenomics. The final version was published online in 2008 and appeared in the May, 2008 issue of Infection, Genetics and Evolution2.

WP 4: Economic Exploitation and Job Creation The partnership with clinical researchers and industry for commercial innovation is an WP leader: France, Institut Pasteur (IP) important facet of ERA-NET PathoGenoMics. In addition to promoting the transfer of The purpose of this work package was to facilitate communication and interaction with information and know-how from researchers to innovators, the programme encouraged industry in order to create a favourable environment for innovation and commercialization. the establishment of ongoing ties between academia and industry. ERA-NET PathoGenoMics formed a group of experts from industry, academia, clinical For the second and third Joint Transnational Calls (JTCs), each consortium was required research institutions and technology transfer agencies, which discussed the issue of to demonstrate a close collaboration between academic and clinical and/or industrial innovation at two workshops held in Paris. The group met for the first time on November partners. This strategy led to a significant increase in the participation of industrial 2005 at a conference entitled "PathoGenoMics Innovation Partners (PIPs)". Technology partners: fourteen-fold in the second JTC and six-fold in the third JTC, relative to the first transfer officers from various European organisations were invited to explore possible JTC. The same trend was observed for the participation of clinical partners, with an increase future actions in the field of pathogenomics. A second meeting was held in October 2006 of 1.5 and 1.75 fold in the second and third JTCs, respectively. at the Institut Pasteur, Paris. Following the workshops and an extensive survey of the field, an innovation strategy report was published in April 20083. The PathoGenoMics innovation strategy keeps the innovation partners (technology transfer officers, scientists, industrials, and clinicians etc.) informed on related events and to create opportunities for discussion and interaction by organising forums, meetings and courses. It also launched an innovation website, which includes, inter alia, an industry database, technology transfer opportunities, innovation news and events, publications, information on PIP meetings and other useful links. The ERA-NET PathoGenoMics innovation website can be found at: http://www.pathogenomics-era.net/innovation/.

1 | Demuth, A. et al, Op.Cit. 2 | Demuth, A. et al, Op.Cit. 3 | ERA-NET Pathogenomics Innovation, Op.Cit. (http://www.pathogenomics-era.net/ innovation/index.php?index=88) ERA-NET ERA-NET PathoGenoMics PathoGenoMics WP5: SUPPORT FOR TRANSNATIONAL CONSORTIUM BUILDING ERA-NET WP5: SUPPORT FOR TRANSNATIONAL|12 CONSORTIUM BUILDING 13 | 1. Introduction / Objectives: PathoGenoMicsWP 5: Support for Transnational The ERA-NET PathoGenoMis aims at networking the research activities carried out at national level in theChristinefield of pathogenomics. The 1. Introduction / Objectives:most important means to implementConsortiumjoint research Buildingactivities is via the joint calls within the research fundersJosenhans,. 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W o r k s h o p held in 2006. Workshop heldW o r k s h oin p held2008in 2008. . fair The workshop was useful in The objectives of this workshop were clearly 11 22 13Partnering2 Workshop held in 2006. Partnering Workshop held in 2008. -2 planning a proposal for the call Overall impression of this The workshop metpoor my expectations workshop 19 24 3 1 stated 0 % 20 % 40 % 60 % 80 % 100 % The workshop was useful in 0 % 20 % 40 % 60 % 80 % 100 % 3. Research Marketplaceplanning a proposal for the3 call. Research Marketplace11 22 13 2 The workshop met my expectations 0 % st 20 % 40 % 60 % 80 % 100 % ConnectedFig. 2 - Feedbackto the thirdfromjointthecall,participantsa ResearchofMarketplacethe 1 Partneringwas implemented in the PathoGenoMicsFig. 4website- Feedback. It aimedfrom atthefacilitatingparticipantstheof the 2nd Partnering 0 % 20 % 40 % 60 % 80 % 100 % Connected to the third joint call, a Research Marketplace was implemented in the PathoGenoMics website. 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ExperiencesMarketplace Special partnering workshops related to the4. multinationalExperiences consortia building for the joint calls may be useful when implemented in fairly new research fields and research traditions. H o w e v e r , since the total costs of such a meeting for the organizers and participants are Connectedrelativelyto thehigh,thirdthe rationalejoint call,of sucha Researcha meetingSpecialshouldMarketplacepartneringbeworkshopscarefullyrelatedwasconsideredto the multinationalimplemented. consortia building forinthethejoint callsPathoGenoMicsmay be useful when implementedwebsitein fairly . It aimed at facilitating the In a case a partnering3. workshopResearchwill be organized,Marketplacenew researchourfields andexperiencesresearch traditionsare. H o wadvised e v e r , since thetototalbecostsconsideredof such a meeting: Thefor theaimorganizersof andtheparticipantsmeetingare should be exchangeclarifiedof researchto all participantsideas (meetingand effectiveis differentrelativelyplanningfromhigh, theregularrationaleof ofscientificcollaborativesuch a meetingmeetings)should be carefullyprojects. Also,consideredthe. asvenuewellshouldas tobe easilyfosterreachablethe assembly. Optimum of consortia and the integrationtimeofforpartnerssuch a meetingwhowouldhavebenotaboutbeentwoIninvolvedmonthsa case a partneringbeforeinworkshopmultilateralthewilldeadlinebe organized,ofourconsortiaproposalexperiences aresubmissionsadvisedso farto be. consideredAll. Inpotential:additionThe aim of thetomeetingprojectformalshouldsessions,bepartnerstimewere invited to register in an electronicfor socializingtoolwouldandalsosubmitConnectedbe importantan Expression. to clarifiedtheoftothirdallInterestparticipantsjoint(meeting. iscall,different afromResearchregular scientific meetings)Marketplace. Also, the venue should be easilywasreachableimplemented. Optimum in the PathoGenoMics website. It aimed at facilitating the exchange of researchtime for such a meetingideaswould be aboutandtwo monthseffectivebefore the deadlineplanningof proposal submissionsof. Incollaborativeaddition to formal sessions, timeprojects as well as to foster the assembly of consortia and the for socializing would also be important. 4. Experiences integration of partners who have not been involved in multilateral consortia so far. All potential project partners were invited to register in an electronic tool and submit an Expression of Interest. Special partnering workshops related to the multinational consortia building for the joint calls may be useful when implemented in fairly new research fields and research traditions. H o w e v e r, since the total costs of such a meeting for the organizers and participants are relatively high, the rationale4. Experiencesof such a meeting should be carefully considered. In a case a partnering workshopSpecialwillpartneringbe organized,workshopsour experiencesrelated toaretheadvisedmultinationalto be consideredconsortia: Thebuildingaim of forthethemeetingjoint shouldcalls maybe be useful when implemented in fairly clarified to all participants (meeting is different from regular scientific meetings). Also, the venue should be easily reachable. Optimum new research fields and research traditions. H o w e v e r, since the total costs of such a meeting for the organizers and participants are time for such a meeting would be about two months before the deadline of proposal submissions. In addition to formal sessions, time for socializing would also berelativelyimportanthigh,. the rationale of such a meeting should be carefully considered. In a case a partnering workshop will be organized, our experiences are advised to be considered: The aim of the meeting should be clarified to all participants (meeting is different from regular scientific meetings). Also, the venue should be easily reachable. Optimum time for such a meeting would be about two months before the deadline of proposal submissions. In addition to formal sessions, time for socializing would also be important. |14 15 |

WP 6: Human Resource Development PhD Awards 2008: conference, Paris Marie Bouvier, Paris, France and Mobility Cristina Dias Rodrigues, Portugal WP Leader: Austria, Federal Ministry for Science and Research (BMWF) Sascha Thewes, Germany As part of the joint strategy to develop human resources, ERA-NET placed a special emphasis on supporting young researchers. The ERA-NET PathoGenoMics annual "PhD Award” was initiated to recognize up to three of the most outstanding PhD theses in the field of genome research on human-pathogenic microorganisms (bacteria and fungi). To be eligible for the award, the PhD thesis had to be completed in the previous year and the research conducted in one of the ERA-NET PathoGenoMics partner countries. The calls for the award were issued annually six years running, from 2006 to 2011 and were bestowed on 17 recipients from six partner countries. The awards of €2000 each, as well as registration and travel expenses to the conference for their recipients were covered by the ERA-NET. This recognition not only encouraged the recipients to pursue their career in science but also gave them an opportunity to present their work at international conferences in the field of microbiology and genomics, such as the FEMS Congress of European Microbiologists, the European Conference on Prokaryotic Genomics and the Genome 2008 Conference.

List of ERA-NET PathoGenoMics PhD award winners and scientific conference: PhD Awards 2006: FEMS congress, Madrid Dr. Alejandro Toledo Arana, Spain Dr. Verena Grimm, Germany PhD Awards 2009: FEMS congress, Gothenburg Eric Alix, France Michal Feldman, Israel Matej Butala, Slovenia

PhD Awards 2007: Prokagen conference, Göttingen Christel Archambaud, France Cédric Delevoye, France Joâo Paulo dos Santos Gomes, Portugal |16 17 |

PhD Awards 2010 :EuroPathoGenoMics Network of Excellence, (NoE) Conference, Pecs WP7:‏ Management Concepts and Tools Itay Tirosh, Israel Andreja Kovač, Slovenia for Transnational Activities Cristina Latasa, Spain WP‏ 8: Implementing Transnational Research and Training WP Leader: Spain, Ministry of Science and Innovation (MICINN) ERA-NET PathoGenoMics established and developed the framework for coordinating, supporting and monitoring three joint calls published on both national and international platforms. The launch of joint transnational calls involved the establishment of preliminary concepts and tools into a framework capable of handling transnational activities. Discussions were required to articulate procedures for implementing and administering joint funding activities, and to formulate contractual and legal frameworks for transnational collaboration. The final outcome of these deliberations was a Memorandum of Understanding (MoU) signed by all partners and detailed instructions on the application procedures. Specific documents, such as the rules for administering the call were consensually formulated by the partners. The relations between the various stakeholders were elaborated. Guidelines for applicants and evaluators were set out and a joint evaluation system was established. A scientific committee of 12-15 international experts in patghogenomics, entitled the Scientific Advisory Board (SAB), was assembled to review the PhD Awards 2011: FEMS conference, Geneva applications. Following the recommendations resulting from the scientific review of the Roland Christian Arnold, Germany applications, funding was provided for collaborative transnational projects based on the Enrique Calvo Alcocer, Spain quality of the applications and the availability of national budgets. Alexandra Isabel Cardoso Nunes, Portugal The projects had to be based on genome-wide approaches and demonstrate close cooperation between academic and clinical or industrial participants. They had to present potentially compelling findings and demonstrate a clear benefit to the public. The Call Secretariat was responsible for administration of the calls, i.e., publishing the calls and receiving the submitted proposals. In addition, the Secretariat functioned as a help desk for applicants, and was responsible for corresponding with the applicants throughout the call processes and project implementation process. Evaluation of Submitted Proposals: The evaluation of the proposals was initiated by a formal check by the Joint Call Secretariat (JCS) and the funding organizations on the eligibility of the applicants and the entire consortia. Funding decisions were made by two organs: the Call Steering Committee (CSC), which comprised NSC members from countries/regions participating in the JTC and the Scientific Advisory Board (SAB), an expert committee of 12-15 international scientific experts nominated by the CSC for their scientific and technical expertise in the field. The SAB was responsible for the assessment of the submitted proposals and for the monitoring and evaluation of the funded projects. For the first call, project evaluation followed a one-step procedure, namely only full proposals were sent for evaluation to the SAB which recommended funding of the selected proposals and articulated a ranking list prioritizing the proposals for funding. In light of the experience gained from the first call and expectations that the number of applications to be received in the subsequent calls would be too large to handle, the vetting procedure for the second and |18 19 |

third calls was revised to a two-step procedure. ‏Outcome of the ERA-NET PathoGenoMics Joint Transnational Calls: After the eligibility check, preliminary "pre-proposals" were submitted to a smaller panel JTC 1 2 3 of five or six SAB members ("Core SAB") for scientific review. The Core SAB's scientific Year 2006 2008 2010 Total assessment was sent on to the Transnational Task Force TTF (consisting of delegates of the CSC in charge of administrative issues on the national level) and returned to the Call Secretariat, which invited those passing the initial scientific screening to submit full Funded projects 12 13 9 34 proposals. The full proposals were sent to the SAB plenum (12-15 members) for final evaluation and ranking. The recommendations and ranking list of the SAB on selected projects were submitted to the Call Steering Committee for final funding approval.SAB Participants 85 77 49 211 members, being involved in the evaluation process as scientific advisors, were not eligible to be partners in proposals responding to the calls and had to sign a declaration of no conflict of interest and confidentiality. Public funding (M€) 16.6 16.3 9 41.9 After receiving the recommendations and ranking list from the SAB, the CSC had to make the final funding decisions, navigating between the available national budgets and the order set in the ranking list provided by the SAB. The CSC was also required to relate to Microorganisms Studied in the ERA-NET PathoGenoMics Joint Calls national requirements, the funding contracts signed with the researchers and of the 2006 2008 2010 administration of periodic reporting.

M. tuberculosis Formal Call asessment Core SAB Secretariat Escherichia coli Haemophilus (5-6 broad scope, Helicobacter Neisseria Pre- Legionella high level experts) Chlamydia Pseudomonas TTF proposals Helicobacter Scientific Listeria Chlamydia Chlamydia asessment Enterococcus Clostridium Proposal of extended SAB Invitation for Brucella proposals Streptococcus Streptococcus Coxiella Pneumocyctis Aspergillus Full Staphylococcus proposals Candida Fusarium Extended SAB Call Aspergillus (12-15 high level Secretariat Candida experts)

Evaluation Funded Ranking proposal list CSC

Structure of Call Management, Used in the ERA-NET PathoGenoMics Joint Calls. SAB- Scientific Advisory Board; TTF- Transnational Task Force (representatives of funding agencies); CSC- Call Steering Committee

Submissions to the ERA-NET PathoGenoMics Joint Transnational Calls

JTC 1 2 3 Year 2006 2008 2010 Total

Pre-proposals 44* 50 50 144

Participants 217 286 253 756

Requested budget 40.3 64.6 63.7 168.6

‏* The first call in 2006 did not include a pre-proposal stage. A total of 44 proposals were submitted. ERAERA--NETNET PathoGenoMicsPathoGenoMics

CONSORTIACONSORTIA COMPOSITION COMPOSITION

1.1. TheThe numbernumber ofof participatingparticipating countriescountries perper 4.417. 17outoutofof3434consortiaconsortiaincludedincludedcliniciansclinicians consortiumconsortiumrangedrangedfromfrom33toto7.7. ERAERA-PathoGenoMics-PathoGenoMics implementedimplemented thethe directdirect interactioninteraction ofof TableTable1 –1Participating– Participatingcountriescountriesperperconsortiumconsortium interdisciplinaryinterdisciplinarygroups,groups,includingincludingcliniciansclinicians. .1717outoutofof3434consortiaconsortia establishedestablishedpartnershipspartnershipswithwithcliniciansclinicians(Fig(Fig. .3).3).SomeSomeofofthesethese CallCall ConsortiumConsortium acronym acronym AUAUBE BEDE DEDKDKES ESFI FRFI FRHUHUIL PTIL PTSI SESI SEUKUKUSAUSA ERAERA-HELDIVNETNET-HELDIVNETNET DE DE FI FRFI FR PT PT interactionsinteractionswereweredonedonethroughthroughthetheestablishmentestablishmentofofconnectionsconnectionswithwith PneumocystisPneumocystis ES ES FR FR USAUSA hospitalshospitalsthatthatdiddidnotnotbelongbelongtotothetheconsortiaconsortia. . PathogenomicsPathogenomics FunPathFunPath AUAU DE DE ES ES FR FR EPSEPS-MATRIX-MATRIX ES ES FR FR UK UK 7 7 7 7 PathoGenoMicsPathoGenoMicsGLYCOSHIELDGLYCOSHIELD DE DE ES ES FR FR 6 6 1st 1st FaecalVirFaecalVir DE DE ES ES FR FR PT PT 6 6 KinCanKinCan DE DE FR FR IL IL 5 5 ECIBUGECIBUG AUAU DE DE FI FRFI FR 4 4 PathoStrepPathoStrep DE DE FR FR IL IL 4 4 X X DE DE FI FRFI FRHUHUIL IL SE SE 3 3 RNAiRNAi-Net-Net AUAU DE DE ES ESFI FRFI FR IL PTIL PT 2 2 CONSORTIACONSORTIASPATELISSPATELIS DE DECOMPOSITION COMPOSITIONES ES FR FR IL PTIL PT partners clinical partners clinical CoMeVacCoMeVac BE BEDE DE FI FRFI FR 1 1 FunGenFunGen DE DE ES ES FR FR with of consortia Number with of consortia Number 0 0 UTIUTI-Interference-Interference DE DE FI FI HUHUIL IL SE SE 1st 1stCall Call 2nd2nd Call Call 3rd3rd Call Call ADHRESADHRES DK DKES ES FR FR PT PT sncRNAomicssncRNAomics DE DE FR FR SI SI Fig.Fig.3 -3Number - Number of ofconsortia consortia integrating integrating clinical clinical partners. partners. TRANSPATTRANSPAT AUAU DE DE ES ES FR FR 2nd 2nd ANTIFUNANTIFUN DE DE ES ES FR FR 1.1. TheThe numbernumber ofof participatingparticipating countriescountriesCDIFFGENCDIFFGEN perperAUAU DE DE 4FR.4FR17. 17outPT PTSIoutSIofof3434consortiaconsortiaincludedincludedcliniciansclinicians ChlamyTransChlamyTrans AUAU DE DE FI FI HUHU consortiumconsortiumrangedrangedfromfrom3 3toto7.7. StreptomicsStreptomics AUAU FI FRFI FR PATHOMICSPATHOMICS AUAU DE DE ES ES FR FRERAERA-PathoGenoMics-PathoGenoMics implementedimplemented5.5.the1818the(outdirect(outdirectofofinteraction34interaction34) )consortiaconsortiaof of includedincludedpartnerspartnersfromfrom TableTable1 –1Participating– Participatingcountriescountriesperperconsortiumconsortium METAGUTMETAGUT AUAU DE DE ES ES interdisciplinaryinterdisciplinaryPT PT groups,groups,includingincludingclinicianscliniciansindustryindustry. 17. 17outoutof of3434consortiaconsortia COLIEVOLCOLIEVOL AUAU DE DE ES ES FR FRestablishedestablishedpartnershipspartnershipswithwithcliniciansclinicians(Fig(Fig. .3).3).SomeSomeof ofthesethese CallCallConsortiumConsortium acronym acronym AU AUBE DEBE DKDE ESDK FIESFRFI HUFR HUIL PTIL SIPTLISTRESSSESILISTRESSUKSE UKUSAUSA DE DE ES ES FR FR IL PTIL PT HELDIVNETHELDIVNET DE DE FI FRFI FR PT PTaspBIOmicsaspBIOmics AUAU DE DE ES ES FR FRinteractionsinteractionswereweredonedonethroughthroughthetheestablishmentestablishmentAmongAmongthetheof3434ofconnectionsPathoGenoMicsconnectionsPathoGenoMicswithwithfundedfundedprojects,projects,1818consortiaconsortiaincludedincluded PneumocystisPneumocystis OXYstressOXYstress AUAU DE DE ES ES ES ESFR FR USAUSA hospitalshospitalsthatthatdiddidnotnotbelongbelongto tothetheconsortiaconsortia. . PathogenomicsPathogenomics HELDIVPATHELDIVPAT DE DE FR FR PT PT partnerspartnersfromfromindustryindustry(Fig(Fig.4)..4).A Atotaltotalnumbernumberofof2121companiescompanies rd rd FunPathFunPath AU AU DE DE ES ESFR FR 3 3 MobileGenomicsMobileGenomics AUAU DE DE FR FR integratedintegratedthethe1818fundedfundedconsortiaconsortiaofofthethethreethreecallscalls(Fig(Fig.5.and5 andtabletable2).2). ARMSAARMSA ES ES FR FR PT PT 7 7 EPS-EPSMATRIX-MATRIX ES ESFR FR UK UK TheTheindustryindustryparticipationparticipationrangedrangedfromfrom1 to1 to3 companies3 companiesperperconsortiumconsortium. . GLYCOSHIELDGLYCOSHIELD DE DE ES ESFR FR CELLPATHCELLPATH DE DE ES ES FR FR PT PT 7 7 6 6 1st 1st FaecalVirFaecalVir DE DE ES ESFR FR PT PTGeMoAGeMoA DE DE ES ES FR FR 6 6 CANDICOLCANDICOL AUAU DE DE FR FRHUHU 14 14 KinCanKinCan DE DE FR FR IL IL 11 11 5 5 4 4 12 12 14 14 ECIBUGECIBUG AU AU DE DE FI FRFI FR TheThecoordinatorcoordinatorcountrycountryof theof theconsortiumconsortiumis indicatedis indicatedin boldin boldandandblueblue. . PathoStrepPathoStrep DE DE FR FR IL IL 4 4 10 10 12 12 X X DE DE FI FRFI HUFR HUIL IL SE SE 3 3 8 8 10 10 RNAiRNAi-Net-Net AU AU DE DE ES FIESFRFI FR IL PTIL PT 2 2 6 6 8 8 6 6 SPATELISSPATELIS DE DE ES ESFR FR IL PTIL PT partners clinical partners clinical 6 6 CoMeVacCoMeVac BE DEBE DE FI FRFI FR 1 1 6 6

Number of consortia with of consortia Number with of consortia Number 4 4 FunGenFunGen 2DE.2DE.TheESTheESFRmajorityFRmajorityofofthetheconsortiaconsortiawaswascomposedcomposedbyby0 0 4 4 UTI-UTIInterference-Interference DE DE FI FI HU HUIL IL SE SE 1 1 1 1 1st Call1st Call2nd 2ndCall Call3rd Call3rd2 2 Call 2 2 industry participation industry participation industry

ADHRESADHRES DK ESDK ESFR FR PT PT of companies Number of companies Number researchersresearchersfromfrom33oror44countriescountries. . with of consortia Number with of consortia Number 0 0 0 0 sncRNAomicssncRNAomics DE DE FR FR SI SI Fig.Fig.3 - Number3 - Number of consortia of consortia integrating integrating clinical clinical partners. partners. TRANSPATTRANSPAT AU AU DE DE ES ESFR FR 1st 1stCall Call 2nd2nd Call Call3rd3rd Call Call 1st 1stCall Call 2nd2nd Call Call 3rd3rd Call Call 2nd 2nd ANTIFUNANTIFUN DE DE ES ESFR FR CDIFFGENCDIFFGEN AU AU DE DE FR FR PT SIPT SI 3% 3%3% 3% Fig.Fig.4 -4Number - Number of of consortia consortia with with industrial industrial Fig.Fig.5 -5Number - Number of ofparticipating participating companies. companies. ERA-NET ChlamyTransChlamyTrans AU AU DE DE FI FI HU HU 12%12% partners.partners. StreptomicsStreptomics AU AU FI FRFI FR 41%41% 3 countries3 countries PATHOMICSPATHOMICS AU AU DE DE ES ESFR FR 5.518. 18(out(outofof3434) )consortiaconsortiaincludedincludedpartnerspartnersfromfrom 4 countries4 countries METAGUTMETAGUT AU AU DE DE ES ES PT PT industry5 countriesindustry5 countries TwoTwoconsortiaconsortiafromfromthethefirstfirstcallcallalsoalsoestablishedestablishedinteractionsinteractionswithwith COLIEVOLCOLIEVOL AU AU DE DE ES ESFR FR 41%41% PathoGenoMicsLISTRESSLISTRESS DE DE ES ESFR FR IL PTIL PT 6 countries6 countries companiescompaniesthatthatdiddidnotnotdirectlydirectlyintegrateintegratethetheprojectproject. . aspBIOmicsaspBIOmics AU AU DE DE ES ESFR FR Among7 countriesAmong7 countriesthethe3434PathoGenoMicsPathoGenoMicsfundedfundedprojects,projects,1818consortiaconsortiaincludedincluded OXYstressOXYstress AU AU DE DE ES ES partnerspartnersfromfromindustryindustry(Fig(Fig.4).4)A. Atotaltotalnumbernumberof of2121companiescompanies HELDIVPATHELDIVPAT DE DE FR FR PT PT TableTable2–2Participating– Participatingcompaniescompaniesin thein theconsortiaconsortia. . 3rd 3rd MobileGenomicsMobileGenomics AU AU DE DE FR FR integratedintegratedthethe1818fundedfundedconsortiaconsortiaof ofthethethreethreecallscalls(Fig(Fig.5 .and5 andtabletable2).2). ARMSAARMSA ES ESFRFig.Fig.FR 1 - 1Proportion PT- ProportionPT of ofthe the PathoGenoMics PathoGenoMics consortia consortia with with 3, 4,3, 5,4, 65, or 6 or7 countries. 7 countries. CallCall CompanyCompany CountryCountry TheTheindustryindustryparticipationparticipationrangedrangedfromfrom1 to1 to3 companies3 companiesperperconsortiumconsortium. . CELLPATHCELLPATH DE DE ES ESFR FR PT PT 1st 1st GesellschaftGesellschaft für fürBiotechnologische Biotechnologische Forschung Forschung GmbH GmbH GermanyGermany ERA-NETGeMoAGeMoA DE DE ES ESFR FR CONSORTIA COMPOSITION Bio-BioIliberis-Iliberis14 R&D14R&D SpainSpain CANDICOLCANDICOL AU AU DE DE FR HUFR HU 11 11 12 12 14 14 TheThecoordinatorcoordinatorcountrycountryof theof theconsortiumconsortiumis indicatedis indicatedin boldin boldandandblueblue. . BioAllianceBioAlliancePharmaPharma FranceFrance 10 10 12 12 ProcomcureProcomcureGmbHGmbH AustriaAustria 3.3The. Themajoritymajorityofofthetheconsortiaconsortiainvolvedinvolved66partnerspartners 10 10 PathoGenoMics 8 8 medacmedacGmbHGmbH GermanyGermany 6 6 8 8 6 6 6 6 BacterialBacterial Vaccine Vaccine Program, Program, GlaxoSmithKline GlaxoSmithKline Biologicals BiologicalsSA SA BelgiumBelgium WithinWithinthethethreethreecalls,calls,thetheconsortiaconsortiaconsistedconsistedofofresearchresearchteamsteamsfromfrom3 3 6 6 |20 214 | 4 RNAxRNAxGmbHGmbH GermanyGermany 1. The number of participating countries2.2.TheThepermajoritymajorityof4.of17thetheoutconsortiaconsortiaof 34toconsortiato1616waslaboratorieswaslaboratoriescomposedcomposedincluded. The. Themajoritymajoritycliniciansbyby ofofthetheconsortiaconsortia(47(47%)%)involvedinvolved6 6 4 4 1 1 1 Life1 Life Sequencing Sequencing S.A. S.A. SpainSpain 2 2 2 2 2nd 2nd partnerspartners(Fig(Fig. 2.).2). participation industry participation industry consortium ranged from 3 to 7. of companies Number of companies Number AnagnosticsAnagnosticsBioanalysisBioanalysisGmbHGmbH

Number of consortia with of consortia Number with of consortia Number AustriaAustria researchersresearchersfromfromTheERA3 majority3or-PathoGenoMicsor of4 the4countries consortiacountries was composed. implemented. by The majoritythe of directthe consortia involvedinteraction 6 partners of0 0 0 0 1st Joint Call (2006) researchers from 3 or 4 countries. LifewizzLifewizzLdaLda PortugalPortugal Table 1 – Participating countries per consortium CONSORTIAinterdisciplinary COMPOSITIONgroups, including clinicians. 17 out of 34 consortia 1st Call1st Call2nd 2ndCall Call3rd Call3rd Call 1st Call1st Call 2nd 2ndCall Call 3rd Call3rd Call Theme: Global methods and genome-based approaches to study bacterial established partnerships with clinicians (Fig. 3). Some of these Merck,Merck, Sharp Sharp & Dohme & Dohmede España,de España, S.A. S.A. SpainSpain and fungal human pathogens 3% 3%3% 3% 3% 3% FebitFebitBiomedBiomed GmbH GmbH GermanyGermany Call Consortium acronym AU BE DE DK ES FI FR HU IL PT SI SE UK USA 3% 3% Fig.3 partners3Fig. partners4 - Number4 - Number of ofconsortia consortia with with industrial industrial Fig.Fig.5 - Number5 - Number of participating of participating companies. companies. 2nd Joint Call (2008) interactions were done through the establishment9% 9%6% 6%6%of6%connections with HELDIVNET DE FI FR PT 12%12% partners.4 partners4partners. partners 12%12% GenedataGenedataBioinformatikBioinformatikGmbHGmbH GermanyGermany Theme:Pneumocystis Applied pathogenomics: Prevention, diagnosis, treatment and 41%41% 3 countries3 countries ES FR USA hospitals that did not belong to the consortia14%14% . 5 partners5 partners Pathogenomics 4 countries4 countries IntercellIntercellAGAG AustriaAustria monitoring of infectious diseases in humans 6 partners6 partners FunPath AU DE ES FR 5 countries5 countries TwoTwoconsortiaconsortiafromfromthethefirstfirstcallcallalsoalsoestablishedestablishedBayerBayer interactionsCropScience CropScienceinteractionsSA SA withwith FranceFrance 3rd Joint Call (2010) 7 7 partners7 partners EPS-MATRIX ES FR UK 41%41% 1.Theme:The Translationalnumber pathogenomics: Prevention,of diagnosis,participating treatment countries per 4. 17 out 6of countries6 countries34 consortia included47%47% clinicians bioMérieuxbioMérieux FranceFrance GLYCOSHIELD DE ES FR 7 6 companies8 partnerscompanies8 partners thatthatdiddidnotnotdirectlydirectlyintegrateintegratethetheprojectproject. . st and monitoring of infectious diseases in humans ERA-NET 7 countries7 countries 1 FaecalVirconsortium rangedDE ES fromFR PT3 to 7. 6 9 partners9 partners LabDiaLabDiaLabordiagnostikGmbHLabordiagnostikGmbH AustriaAustria KinCan DE FR IL ERA-PathoGenoMics implemented the direct≥10≥10 partners partnersinteraction of 5 4 AppliedApplied Research Research using using Omic OmicSciencesSciences S.L. S.L. (AROMICS) (AROMICS) SpainSpain ECIBUG AU DE FI FR interdisciplinary groups, including clinicians. 17 outTableofTable234– Participating2–consortiaParticipatingcompaniescompaniesin thein theconsortiaconsortia. 3.rd 3rd PathoStrep Table 1 – ParticipatingDE countriesFR PathoGenoMicsIL per consortium Proportion of the PathoGenoMics consortia 4 Proportion of the PathoGenoMics consortia with GlaxoSmithKlineGlaxoSmithKline Tres TresCantosCantos Medicnes MedicnesDevelopmentDevelopment Centre Centre (GSK (GSK TCMDC) TCMDC) SpainSpain Fig.Fig. 1 - Proportion1 - Proportion of theof the PathoGenoMics PathoGenoMics consortia consortia with with 3, 4, 3, 5, 4, 6 5, or 6 7or countries. 7 countries. CallCallCompanyCompany CountryCountry X DE FI FR HU IL SE with 3, 4, 5, 6 or 7 countries. FigestablishedFig. 2.-2Proportion- Proportion3 partnershipsof ofthethePathoGenoMics3, PathoGenoMics4, 5, 6, 7,with 8, 9 or morecliniciansconsortia thanconsortia 10 rsearchwithwith(Fig partners.3, 34., 453, )56., 67,Some78, 89, or9 ormoreofmorethesethanthan1010 DanoneDanoneResearchResearch FranceFrance RNAi-Net Call ConsortiumAU DE acronymES FI FR AU ILBEPTDE DK ES FI FR HU IL PT SI SE UK USA 1st 1st GesellschaftGesellschaft für Biotechnologischefür Biotechnologische Forschung Forschung GmbH GmbH GermanyGermany researchinteractionsresearchpartnerspartners2 were. . done through the establishment of connections with EvocatalEvocatalGmbH,GmbH, Düsseldorf Düsseldorf GermanyGermany DistributionSPATELIS of research groups: HELDIVNETDE ES FR IL PTDE FI FR PT partners clinical Pneumocystis RESEARCH SUBJECTS 1 Bio-BioIliberis-IliberisR&DR&D SpainSpain CoMeVac BE DE FI FR ES FR USA hospitals that did not belong to the consortia.

Pathogenomics with of consortia Number FunGen DE ES FR 74% of the funded projects were on bacteria research.0 17 out of 34 consortia included clinicians BioAllianceBioAlliancePharmaPharma FranceFrance FunPath AU DE ES FR UTI-Interference The ERA-NETDE PathoGenoMicsFI HU ILfunds researchSE on genomics of human pathogens, focusing on Bacteria and Fungi. 1st Call 2nd Call 3rd Call 7 ProcomcureProcomcureGmbHGmbH AustriaAustria ADHRES EPS-MATRIX DK ES FR PT ES 3.FR3The. ThemajoritymajorityUK ofofthetheconsortiaconsortiainvolvedinvolved6 6partnerspartners 7 6 medacmedacGmbHGmbH GermanyGermany sncRNAomics GLYCOSHIELDDE FR DESI ES FR st Bacteria Fungi 1 FaecalVir DE ES FR PT Fig. 3 - Number of consortia integrating6 clinical partners. TRANSPAT AU DE ES FR BacterialBacterial Vaccine Vaccine Program, Program, GlaxoSmithKline GlaxoSmithKline Biologicals BiologicalsSA SA BelgiumBelgium 2nd ANTIFUN KinCan DE ES FR DE FR WithinWithinIL thethethreethreecalls,calls,thetheconsortiaconsortiaconsistedconsistedof ofresearchresearchteamsteamsfrom5 from3 3 ECIBUG AU DE FI FR 26% 4 RNAxRNAxGmbHGmbH GermanyGermany CDIFFGEN AU DE FR PT SI to to1616laboratorieslaboratories. The. Themajoritymajorityof ofthetheconsortiaconsortia(47(%47)%involved) involved6 6 PathoStrep DE FR IL 4 Life LifeSequencing Sequencing S.A. S.A. ChlamyTrans From AUthe DEprojectsFI HUfunded 74 % were nd nd SpainSpain X DE FI FR partnersHU partnersIL SE(Fig(Fig. 2)..2). 3 2 2 Streptomics AU FI FR 74% AnagnosticsAnagnosticsBioanalysisBioanalysisGmbHGmbH AustriaAustria PATHOMICS RNAiAU -NetDE ES FR AU DE ES FI FR IL PT 5. 18 (out of 34) consortia included2 partners from SPATELIS DE ES FR IL PT partners clinical LifewizzLifewizzLda Lda METAGUT proposalsFI AU DE onES bacteriaPT research. PortugalPortugal CoMeVac BE DE FI FR 1 COLIEVOL AU DE ES FR industry Merck,Merck, Sharp Sharp & Dohme & Dohmede España,de España, S.A. S.A. SpainSpain FunGen DE ES FR with of consortia Number 0 LISTRESS DE ES FR IL PT 3% 3% FebitFebitBiomedBiomed GmbH GmbH GermanyGermany UTI-Interference DE FI HU IL SE 3% 3% 3 partners3 partners aspBIOmics AU DE ES FR 9% 9%6% 6%6% 6% 1st Call 2nd Call 3rd Call ADHRES DK ES FR PT Among the 34 PathoGenoMics4 partners4 partnersfunded projects, 18 consortia included GenedataGenedataBioinformatikBioinformatikGmbHGmbH GermanyGermany DistributionOXYstress of research groups per countries:AU DE ES 12% 12% BACTERIAsncRNAomics DE HelicobacterFR SI FUNGI 14% 14%partners from industry 5 (Figpartners5 partners.4). A total number of 21 companies HELDIVPAT DE FR PT Salmonella Fig. 3 - Number of consortia integrating clinical partners.IntercellIntercellAG AG AustriaAustria rd TRANSPAT AU DE ES FR 3 MobileGenomics AU DE FR Pseudomonas 6 partners6 partners nd 2% 2% integrated the 18 funded consortia of the three calls (Fig.5 and table 2). BayerBayer CropScience CropScienceSA SA FranceFrance 2 OtherANTIFUN DE ESStaphylococcusFR ARMSA 2% ES FR PT 7 partners7 partners 2% CDIFFGEN7% 10% AU DE EnterococcusFR PT SI 8% 8% 47% 47% Pneumocystis18 (out of 34) consortia included partners from industry CELLPATH 2% DE ES FR5% PT The industry participation8ranged partners8 partnersfrom 1 to 3 companies per consortium. bioMérieuxbioMérieux FranceFrance ChlamyTrans AU7% DE ChlamydiaFI HU GeMoA 5% DE ES FR Streptococcus Candida 9 partners9 partners LabDiaLabDiaLabordiagnostikGmbHLabordiagnostikGmbH Streptomics AU FI FR 14 AustriaAustria CANDICOL AU DE FR HU Escherichia 34% 5% 10% 5. 1811 (out≥10 partners≥10of partners 34 ) consortia included partners from PATHOMICS AU DE ESListeriaFR 12 Cryptococcus 14 AppliedApplied Research Research using using Omic OmicSciencesSciences S.L. S.L.(AROMICS) (AROMICS) SpainSpain 42% 3rd 3rd The coordinator country7% of theMETAGUTconsortium is indicatedAU in5%boldDE andESNeisseriablue. PT Aspergillus GlaxoSmithKlineGlaxoSmithKline Tres TresCantosCantos Medicnes MedicnesDevelopmentDevelopment Centre Centre (GSK (GSK TCMDC) TCMDC) SpainSpain Mycobacterium 10 industry 12 10%COLIEVOL AU DE ES FR 12% Legionella LISTRESS 7% DE ES FR Fig.ILFig2PT.-2Proportion- Proportionof theof8%thePathoGenoMicsPathoGenoMicsconsortiaconsortiawithFusariumwith3, 43,, 54,, 65,, 76,, 87,, 98,or9 moreor 10morethanthan10 10 DanoneDanoneResearchResearch FranceFrance Klebsiella 8 aspBIOmics AU DE ES FR 6 Burkholderiaresearchresearchpartnerspartners. . Among the 34 PathoGenoMics8 funded projects,6 18 consortiaEvocatalEvocatalincludedGmbH,GmbH, Düsseldorf Düsseldorf GermanyGermany OXYstress AU DE ES 6 Clostridium 6 HELDIVPAT DE BrucellaFR PT partners from industry (Fig.4). A total number of 21 companies Proportion of bacteria genera studied. Proportion of fungi genera studied. 4 2. The majority of the3rd consortiaMobileGenomics wasAU composedDE CoxiellaFR by 4 1 integrated the 18 funded consortia of the three calls (Fig.5 and table 2). ARMSA ES FR PT 2 2 1 industry participation industry The industry participationof companies Number ranged from 1 to 3 companies per consortium. researchers from 3 or 4CELLPATHcountries. DE ES FR PT with of consortia Number 0 0 Table 1- ConsortiaGeMoAtitles on bacteria research DE ES FR Table 2 - Consortia titles on fungi research 1st Call 2nd Call 3rd Call 1st Call 2nd Call 3rd Call 14 Parasite and host CANDICOLgenetic diversity in Helicobacter infections.AU DE FR HU • • Pneumocystis Pathogenomics: unravelling the Colonization-to-Disease shift. 11 • Exploring Protein Secretion within the bacterial matrix. 12 14 Large scale screening of potential key factors involved in the / virulence transition of • 3%The 3%coordinator country of the consortium is indicated in bold andGenomicblue Approaches. to Unravel the Molecular Mechanisms of Pathogenicity in the Human Fungal Enterococcus faecalis. • Fig. 4 - Number of consortia with industrial Fig. 5 - Number of participating12 companies. Pathogen Candida glabrata. 10 European Initiative to Fight Chlamydial Infections by Unbiased Genomics. • 12% partners. • A comparative molecular analysis of GAS and GBS pathogenesis. 10 41% 3 countries Surface Modulation of the Fungal & Host Response using a Genomic Approach. 8 • Deciphering the intersection of commensal and extraintestinal pathogenic E. coli. • 6 • A global RNAi approach to unravel eukaryotic host functions 4that countries modulate bacterial infections. 8 6 Systematic analyses of kinase and phosphatase function in morphological, environmental,6 and Spatio-temporal analysis of Listeria-host protein interactions. • • 5 countries virulence responses of the human fungal pathogen Candida albicans. 6 Genome wide screening of the human pathogen Neisseria meningitidis for proteins enhancing serum Two consortia from the first call also established interactions with • 41% resistance and evaluation of their vaccine potential. 6 countries 4 2. The majority of the consortia was composed• Transcriptional networks controllingby virulence in filamentous fungal pathogens. 4 • Functional genomics of host-pathogen interactions using high-throughput screenings: a novel companies that did not directly1 integrate the project. approach towards identifying therapeutic/prophylactic targets.7 countries 1 The cell wall as a target to improve antifungal therapy against Aspergillosis. 2 2

• participation industry Pathogenomic approach to explore the use of bacterial interference as alternative treatment of • of companies Number researchersrecurrent urinary tractfrom infections. 3 or 4 countries. • Invasive aspergillosis: Biomarkers for prevention, diagnosis and treatment responsewith of consortia Number . 0 0 • ADHRES-Signature Project. Table 2– Participating companies in the consortia. • High throughput comparative sncRNAome analysis in major Gram-positive human pathogenic bacteria: • Human fungal pathogens under oxygen stress: adaptive mechanisms to hypoxia and reactive oxygen1st Call 2nd Call 3rd Call 1st Call 2nd Call 3rd Call Fig. 1 - Proportion of thefunctional PathoGenoMics characterization by a systems consortia biology approach with and 3, peptide 4, 5, nucleic 6 or acid 7 drug countries. design. species and their consequences for host interaction and therapy. • Pathogenomic of increased Clostridium difficile virulence. Call Company Country 3% 3% Understanding colonisation and the transition to pathogenic dissemination by Candida species: • Transcriptome-based Monitoring and Eradication of Chronic Chlamydial Infection. • st Fig. 4 - Number of consortia with industrial Fig. 5 - Number of participating companies. • Mechanisms and modulation of innate immune responses to Streptococcus pneumoniae and S. towards early diagnostic and therapeutic approaches.1 Gesellschaft für Biotechnologische Forschung GmbH Germany pyogenes. 12% partners. • Host-pathogen protein-protein interactomes and their influence on the host41% metabolome. 3 countries Bio-Iliberis R&D Spain • Development, prevention and early diagnostic detection of Clostridium difficile-associated pseudomembranous colitis - an interdisciplinary network. 4 countries Escherichia coli CandidaBioAlliancealbicansPharma France • Identification of hot spots of divergence and rapidly changing genes within Shiga toxin-producing 5 countries Escherichia coli. ProcomcureTwoGmbHconsortia from the first call also establishedAustria interactions with 41% 3. The majority of the• Analysisconsortia of the cellular mechanisms underlyinginvolved the early response of the6 hostpartners to stress induced by 6 countries Listeria infection. medac GmbHcompanies that did not directly integrate theGermanyproject. • Helicobacter pylori diversity in pathogenesis, antibiotic resistance, and evasion from natural and 7 countries vaccine-induced immune responses. Bacterial Vaccine Program, GlaxoSmithKline Biologicals SA Belgium Within the three calls, the• Impact consortiaof mobile genetic elementsconsisted and horizontal geneof transferresearch on bacteria-hostteams adaptation: a from 3 genomic v i e w . RNAx GmbH Table 2– Participating companies in the consortiaGermany. to 16 laboratories. The• Globalmajority analysis of antisenseof regulatorythe mechanismsconsortia in (47.%) involved 6 • Characterisation of host cell pathways altered by effectors of Brucella, Chlamydia, and Coxiella: Life Sequencing S.A. Spain partners (Fig. 2). Fig.identification 1 - Proportion of novel therapeutic of thetargets. PathoGenoMics consortia with 3, 4, 5, 6 or 7 countries. 2nd Call Company Country • A genome-wide approach for characterizing the mode of action of novel compounds against Anagnostics Bioanalysis GmbH Austria tuberculosis. 1st Gesellschaft für Biotechnologische Forschung GmbH Germany Lifewizz Lda Bio-Iliberis R&D Portugal Spain Merck, Sharp & Dohme de España, S.A. Spain BioAlliance Pharma France 3% Febit Biomed GmbH Germany 3% 3 partners 9% 6% 6% Procomcure GmbH Austria 3. The majority of the consortia4 partners involved 6 partners Genedata Bioinformatik GmbH Germany 12% medac GmbH Germany 14% 5 partners Intercell AG Austria 6 partners Bacterial Vaccine Program, GlaxoSmithKline Biologicals SA Belgium Within the three calls, the consortia consisted of research teams from 3 Bayer CropScience SA France 7 partners RNAx GmbH Germany to 16 laboratories47%. The majority of the consortia (47%) involved 6 bioMérieux France 8 partners Life Sequencing S.A. nd Spain partners (Fig. 2). 9 partners LabDia LabordiagnostikGmbH2 Austria Anagnostics Bioanalysis GmbH Austria ≥10 partners Applied Research using Omic Sciences S.L. (AROMICS) Spain 3rd Lifewizz Lda Portugal GlaxoSmithKline Tres Cantos Medicnes Development Centre (GSK TCMDC) Spain Merck, Sharp & Dohme de España, S.A. Spain Fig. 2 - Proportion of the PathoGenoMics consortia with 3, 4, 5, 6, 7, 8, 9 or more than 10 Danone Research France 3% Febit Biomed GmbH Germany 3% 3 partners research partners. 9% 6% Evocatal GmbH, Düsseldorf Germany 6% 4 partners 12% Genedata Bioinformatik GmbH Germany 14% 5 partners Intercell AG Austria 6 partners Bayer CropScience SA France 7 partners 47% 8 partners bioMérieux France 9 partners LabDia LabordiagnostikGmbH Austria ≥10 partners Applied Research using Omic Sciences S.L. (AROMICS) Spain 3rd GlaxoSmithKline Tres Cantos Medicnes Development Centre (GSK TCMDC) Spain Fig. 2 - Proportion of the PathoGenoMics consortia with 3, 4, 5, 6, 7, 8, 9 or more than 10 Danone Research France research partners. Evocatal GmbH, Düsseldorf Germany |22 23 |

First Call for Proposals Projects funded: Under the heading; “Global methods and genome-based approaches to study bacterial and Project fungal human pathogens”, the first transnational call for proposals, was issued in 2006. Leader/ The announcement included a list of suggested topics and 44 project applications were Title Coordinator Project Partners submitted, representing a total of 216 participating scientists. Twelve research consortia were chosen for funding for a total sum of approximately €16.6 million. Mark Achtman, DE HELDIVNET: Analysing Cristine Josenhans, DE Sebastian the genetic variability of Rainer Haas, DE Members of the Scientific Advisory Board (SAB) of the first call: Suerbaum, the Helicobacter pylori Agnès Labigne, FR DE Name Institution/company bacterium Marja-Liisa Hanninen, FI José Carlos Machado, PT Prof. Dr. Martin Maiden (chair) University of Oxford, Oxford, United Kingdom Pneumocystis Prof. Dr. Renate Rosengarten University of Veterinary Medicine, Pathogenomics: Eduardo Enrique F. Calderón, ES Vienna, Austria unraveling the Dei-Cas, FR Melanie T. Cushion, USA Colonization-to- Prof. Dr. Matti Sarvas National Public Health Institute, Helsinki, Disease shift Eduard Finland Torrents, Prof. Dr. Didier Mazel Institut Pasteur, Paris, France Spain "Being part of Dr. Klaus-Peter Koller Aventis Deutschland GmbH, Frankfurt, Christophe d’Enfert, FR Germany Genomic Approaches Dominique Ferrandon, FR (associate partner) a consortium to Unravel the Steffen Rupp, DE of young Molecular Mechanisms Bernhard Hube, DE (associate partner) Prof. Dr. Hillel Bercovier Hebrew University of Jerusalem, Jerusalem, Karl Kuchler, of Pathogenicity in Toni Gabaldón, ES scientists Israel AT is also very the Human Fungal Dominique Ferrandon, FR (associate partner) Prof. Dr. Manuel António da Silva Santos University of Aveiro, Aveiro, Portugal Pathogen Candida Christoph Schüller, AT (associate partner) gratifying glabrata - FunPath Ken Haynes, UK (associate partner) scientifically. Brendan Cormack, USA (associate partner) I can now Prof. Dr. Balbino Alarcón Centro de Biología Molecular collaborate “Severo Ochoa”, Madrid, Spain with people Prof. Dr. Tatjana Avsic Zupanc Institute of Microbiology and Immunology, Ljubljana, Slovenia that otherwise Exploring Protein Thierry Jouenne, FR would be out Secretion within the Jean-Marc Alain Filloux, UK Iñigo Lasa, ES Prof. Dr. Lars Engstrand Karolinska Institutet, Stockholm, Sweden bacterial biofilm matrix. Ghigo, FR of reach. This José R Penades, ES broadens Acronym: EPS-Matrix the scope of Prof. Dr. Marta Granström Karolinska Institutet, Stockholm, Sweden research and ultimately Prof. Dr. Wolf-Dietrich Hardt Federal Institute of Technology, Zurich, Switzerland Glycoshield: Surface Joachim F. Ernst, DE produces Modulation of the Guilhem Janbon, FR Steffen Rupp, DE better Fungal & Host Jesus Pla, ES Daniel Poulain, FR science." Response using a Angel Dominguez, ES Genomic Approach Claude Gaillardin, FR

Large scale screening of potential key Yanick Auffray; Pascale Serror, FR factors involved in Axel Hartke, Fátima Lopes, PT the commensalism / FR Johannes Huebner, DE virulence transition of Bruno Gonzales-Zorn, ES Enterococcus faecalis |24 25 |

Project Project Leader/ Leader/ Title Coordinator Project Partners Title Coordinator Project Partners

Matthias Maass, AT Mikael Skurnik, FI, Systematic analyses Pascale Cossart, FR of kinase and David O’Callaghan, FR phosphatase function Martin Aepfelbacher, DE A global RNAi approach in morphological, Ingo B. Autenrieth, DE Robert Joachim Morschhäuser, DE to unravel eukaryotic environmental, and Ilan Rosenshine, IL Arkowitz, FR Daniel Kornitzer, IL host functions that Thomas F. virulence responses Céu Figueiredo, PT modulate bacterial Meyer, DE of the human fungal José Antonio Bengoechea, ES infections (acronym pathogen Candida Francisco García-del Portillo, ES RNAi-Net) albicans Jean-Pierre Gorvel, FR (associate partners) Didier Raoult, FR (associate partners) Philippe Sansonetti, FR (associate partners) Jürgen Heesemann, DE (associate partners) Michael Hensel, DE (associate partners)

Georg Wick, AT Mirja Puolakkainen, FI European Initiative Pia Vuorela, FI to Fight Chlamydial Matthias Agathe Subtil, FR Infections by Unbiased Maass, AT Jens Gieffers, DE Lothar Jänsch/ Uwe Kärst, DE Genomics - ECIBUG - Georg Häcker, DE Dagmar Beier Jürgen Kreft/ Michael Kuhn, DE SPATELIS - “Spatio- Johannes H. Hegemann, DE Trinad Pascale Cossart/ Hélène Bierne, FR temporal analysis of Thomas F. Meyer, DE Chakraborty, Franscisco Garcia -del Portillo, ES Listeria-host protein DE Mariela Scortti, ES interactions” Didier Cabanes, PT Yair Aharonowitz/Roded Sharan, IL

A comparative Philippe Glaser, FR Patrick molecular analysis Bernd Kreikemeyer, DE Andreas Podbielski, DE Trieu-Cuot, of GAS and GBS Emanuel Hanski, IL FR pathogenesis Richard Muench, DE

Jürgen Heesemann/Sören Schubert, DE Helge Karch/M. Alexander Schmidt, DE Till T. Bachmann, UK Maryvonne Moulin-Schouleur/ Philippe Gilot, FR Deciphering the Eric Oswald, FR intersection of Chantal LeBouguénec, FR Jörg Hacker, commensal and Benita Westerlund-Wikström, FI DE extraintestinal Eliora Ron, IL pathogenic E. coli Levente Emödy/István Wittmann, HU Bela Nagy, HU Catharina Svanborg/ Björn Wullt, SE (associate partners) Bernt Eric Uhlin/ Sun Nyunt Wai, SE (associate partners) |26 27 |

All the following project abstracts were written by the project coordinators who are solely humans and Helicobacter pylori. Nature 445: 915-918. responsible for their content  Schwarz, S., G. Morelli, B. Kusecek, A. Manica, F. Balloux, R. J. Owen, D. Y. Graham, S. Project name: Parasite and host genetic diversity in Helicobacter infections van der Merwe, M. Achtman* und S. Suerbaum*. 2008. Horizontal versus familial (Acronym: HELDIVNET) transmission of Helicobacter pylori. PLoS Pathogens 4:e1000180. * corr. authors Coordinator: Sebastian Suerbaum, Institute for Medical Microbiology and Hospital  Wiedemann, T., E. Loell, S. Mueller, M. Stoeckelhuber, M. Stolte, R. Haas, G. Rieder. 2009. Epidemiology, Hannover Medical School, Hannover, Germany Helicobacter pylori cag--dependent early immunological response Partners: Mark Achtman, Dept. Molecular Biology, Max Planck Institute for Infection Biology, triggers later precancerous gastric changes in Mongolian gerbils. PLoS ONE 4:e4754. Berlin, Germany  Rust, M., S. Borchert, E. Niehus, S. A. Kuhne, E. Gripp, A. Bajceta, S. Suerbaum, J. L. Rainer Haas, Dept. Bacteriology, Max von Pettenkofer Institute, Munich, Germany McMurry, K. T. Hughes und C. Josenhans. 2009. The Helicobacter pylori anti-sigma factor Marja-Liisa Hänninen, Dept. of Food and Environmental Hygiene, University of Helsinki, FlgM is predominantly cytoplasmic and cooperates with the flagellar basal body protein Finland FlhAC. J. Bacteriol. 191:4824-4834. Christine Josenhans, Institute for Medical Microbiology and Hospital Epidemiology,  Moodley Y., B. Linz, Y. Yamaoka, H. Windsor, S. Breurec, J.-Y. Wu, A. Maady, S. Bernhöft, J.- Hannover Medical School, Hannover, Germany M. Thiberge, S. Phuanukoonnon, G. Jobb, P. Siba, D. Y. Graham, B. Marshall, M. Achtman. Agnès Labigne, Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, Paris, 2009. The peopling of the pacific from a bacterial perspective. Science 323: 527-530. France  Morelli, G., X. Didelot, B. Kusecek, S. Schwarz, C. Bahlawane, D. Falush, S. Suerbaum und José Carlos Machado, Institute of Molecular Pathology and Immunology, University of Porto, M. Achtman. 2010. Microevolution of Helicobacter pylori during prolonged infection of Portugal single hosts and within families. PLoS Genet. 6:e1001036. Sebastian Suerbaum, Institute for Medical Microbiology and Hospital Epidemiology,  Olbermann, P., C. Josenhans, Y. Moodley, M. Uhr, C. Stamer, M. Vauterin, S. Suerbaum*, Hannover Medical School, Hannover, Germany M. Achtman* und B. Linz. 2010. A global overview of the genetic and functional Abstract: Helicobacter pylori is one of the commonest human pathogens, infecting more diversity in the Helicobacter pylori cag pathogenicity island. PLoS Genet. 6:e1001069. than one half of the world population. H. pylori is responsible for the second highest * corr. authors. number of infection-associated cancers, i.e. 490 000 cases per year world-wide, or 5.4%  O›Toole, P. W., W. J. Snelling, C. Canchaya, B. M. Forde, K. R. Hardie, C. Josenhans, R. L. of all cancers. In addition to gastric adenocarcinoma, H. pylori is also a risk factor for a Graham, G. McMullan, J. Parkhill, E. Belda und S. D. Bentley. 2010. second gastric malignancy, gastric lymphoma of the mucosa-associated lymphoid tissue and proteomics of Helicobacter mustelae, an ulcerogenic and carcinogenic gastric (MALT lymphoma), which constitutes 7.6% of gastric malignancies. Figures available from pathogen. BMC Genomics 11:164. national cancer statistics suggest a total of 35 800 potentially preventable gastric cancer  Kennemann, L., X. Didelot, T. Aebischer, S. Kuhn, B. Drescher, M. Droege, R. Reinhardt, P. deaths in the EU (25 member states) for 2000. Other Helicobacter species cause a variety Correa, T. F. Meyer, C. Josenhans, D. Falush und S. Suerbaum. 2011. Helicobacter pylori of inflammatory diseases in animals and humans. Helicobacter pylori is also one of the genome evolution during human infection. Proc. Natl. Acad. Sci. U.S.A. 108:5033-5038. bacterial species with the highest degree of genetic diversity and variability. The genetic  Breurec, S., B. Guillard, S. Hem, S. Brisse, F. B. Dieye, M. Huerre, C. Oung, J. Raymond, T. S. makeup of both bacterium and host determines the clinical course of H. pylori infection. Tan, J. M. Thiberge, S. Vong, D. Monchy, B. Linz. 2011. Evolutionary history of Helicobacter In this proposal, a group of seven leaders in Helicobacter research from four ERA-NET pylori sequences reflect past human migrations in Southeast Asia. PLoS ONE 6:22058. participating countries have formed a network (HELDIVNET) and used cutting-edge  Schott, T., M. Rossi, M.-L. Hanninen. 2011. Genome Sequence of Helicobacter genomic approaches to achieve a better understanding of a) the global population structure bizzozeroniiStrain CIII-1, an Isolate from Human Gastric Mucosa. J. Bacteriol. 193: of H. pylori, focussing on Africa and Oceania as two regions that promise to reveal key 4565-4566. information about the evolution of H. pylori, b) the functional correlates of H. pylori strain  Moodley, Y., B. Linz, R. P. Bond, M. Nieuwoudt, H. Soodyall, C. M. Schlebusch, S. Bernhöft, variation with respect to virulence and gene regulation, c) the in vivo evolution of the H. J. Hale, S. Suerbaum, L. Mugisha, S. W. van der Merwe und M. Achtman. 2012. Age of the pylori genome during chronic infection as a strategy for adaptation of the pathogen to the association betwen Helicobacter pylori and Man. PLoS Pathog. 8:e1002693 individual host, d) the genomic basis of carcinogenicity in the Mongolian gerbil model of H. Review articles: pylori malignant disease, e) the evolution of the genus Helicobacter by comparative genome  Suerbaum, S. und C. Josenhans. 2007. Helicobacter pylori evolution and phenotypic analysis of yet poorly characterized gastric Helicobacter species with zoonotic potential, f) diversification in a changing host. Nat. Rev. Microbiol. 5:441-452. the role of host genetics in selecting for the type of infecting Helicobacter.  Schweinitzer, T. und C. Josenhans. 2010. Bacterial energy taxis: a global strategy? Arch. Publications related to the funded project (selected): Microbiol. 192:507-520  Linz, B., F. Balloux, Y. Moodley, A. Manica, H. Liu, P. Roumagnac, D. Falush, C. Stamer, F.  Nell, S., S. Suerbaum und C. Josenhans. 2010. The impact of the microbiota on the Prugnolle, S. W. van der Merwe, Y. Yamaoka, D. Y. Graham, E. Perez-Trallero, T. Wadstrom, pathogenesis of IBD: lessons from mouse infection models. Nat. Rev. Microbiol. 8:564- S. Suerbaum, M. Achtman. 2007. An Afr ican origin for the intimate association between 577. |28 29 |

Project name:Genomic Approaches to Unravel the Molecular Mechanisms of Pathogenicity in mammalian hosts: pathogen elimination requires sensing and tasting. Current Opin. the Human Fungal Pathogen Candida glabrata (Acronym: FunPath) Microbiol. 13: 1-8 Coordinator: Karl Kuchler - Medical University Vienna, Max F. Perutz Laboratories, Campus  Schwarzmüller, T., Klein, C. Valachovic, M., & K. Kuchler (2010). Membrane transporters Vienna Biocenter, Austria in pleiotropic drug resistance and stress response in yeast and fungal pathogens. In Partners: Steffen Rupp, IGB Fraunhofer Stuttgart, Germany Transporters as Drug Carriers: Structure, Function, Substrates (Eds Gerhard Ecker and Christophe d’Enfert, Institute Pasteur, France Peter Chiba) WILEY-VCH, Weinheim, pp159-194 Toni Gabaldon (CRG Barcelona, Spain)  Tscherner, M., Schwarzmüller T., & K. Kuchler (2011). Pathogenesis and antifungal drug Associated Partners & International Collaborators resistance of the human fungal pathogen Candida glabrata. Pharmaceuticals 4: 169-186; Bernhard Hube, HKI Jena, Germany doi:10.3390/ph4010169 Dominique Ferrandon, IBMC Strassbourg, France  Hnisz, D., M. Tscherner & K. Kuchler (2011). Targeting chromatin in fungal pathogens as a Christoph Schüller, MFPL, University of Vienna, Austria novel therapeutic strategy: histone modification gets infectious. Epigenomics 3: 129-132 Ken Haynes, University of Exeter, UK  Seider, K., S. Brunke, L. Schild, N. Jablono, O. Majer, D. Barz, A. Haas, K. Kuchler, M. Brendan Cormack, Johns Hopkins University School of Medicine, USA Schaller & B. Hube (2011). The facultative intracellular human fungal pathogen C. Abstract: The molecular mechanisms driving invasion of mammalian hosts by fungal glabrata subverts cytokine response and phagolysosome maturation in macrophages. J. pathogens poses many scientifically challenging problems but are as yet little understood. Immunol. 187:3072-86 The opportunistic human fungal pathogen Candida glabrata is the second-most frequent  Klein, C., K. Kuchler, & M. Valachovic (2011). ABC proteins in yeast and fungal pathogens. cause of candidiasis, causing infections ranging from superficial to life-threatening Essays in Biochem 50: 101-19 systemic diseases of high mortality. The inherent tolerance of C. glabrata to azole drugs  Lesiak-Markowicz, I. G. Vogl, T. Schwarzmüller, C. Speth, C. Lass-Flörl, MP. Dierich, K. makes this pathogen a serious clinical threat. We have constructed a C. glabrata mutant Kuchler, & R. Würzner (2011). C. albicans HGT1 is a multifunctional complement evasion library consisting of 663 confirmed individually genetically bar-coded deletions, each molecule. J. Infect. Disease. 204: 802-809 lacking one specific gene, which now stands as one of the largest deletion collection of a  Tierney, L., L. Rizzetto, D. Cavalieri* & K. Kuchler* (2012). Systems biology of host-fungus eukaryotic pathogen. Functional analysis of this deletion collection in a series of phenotypic interactions: turning complexity into simplicity? Curr Opin Microbiol, in press and fitness assays identified a number of novel genes involved in tolerance to clinically Jose Antonio  Schwarzmüller, T., Ma, B. W. Glaser, B. Cormack, C. D’enfert, Ferrandon, D., C., S. Rupp, important antifungal drugs such as azoles and echinocandins. Moreover, the extensive Bengoechea, K. Haynes, B. Hube, T. Gabaldon, & et al., & K. Kuchler (2012). Systematic analysis of a phenotypic profiling (morphology, growth and fitness in vitro, metal ion sensitivity, oxidative, Spain genome-scale deletion collection of the human fungal pathogen C. glabrata identifies heat, osmo- as well as pH stress, cell integrity and signaling, host cell interaction) identifies "In the status novel genes implicated in antifungal drug resistance. In preparation numerous novel genes implicated in C. glabrata pathobiology. This project demonstrates seminars we  Seider, K., S. Brunke, T. Schwarzmüller, D. Barz, S. Rupp, K. Kuchler, & B. Hube (2012). the potential of a C. glabrata mutant collection as a valuable resource to exploit functional are exposed to Immune evasion, stress resistance and efficient nutrient acquisition are crucial for comparative genomics and systems biology approaches with other fungal pathogens such state-of-the- intracellular survival of C. glabrata within macrophages. In preparation art research as C. albicans to gain a better understanding of infectious diseases caused by Candida  Schwarzmüller, T., W. Glaser, F. Istel, I. Jacobson, S. Rupp, E. Hiller, B. Hube & K. Kuchler and have the spp. This project paved the way for future work to delineate the molecular mechanisms of opportunity (2012). The CBK1 RAM network kinase modulates fungal virulence and is required for the most important genes, which ultimately is expected to facilitate the development of to discuss primary septum formation in C. glabrata. In preparation improved therapeutic approaches to combat fungal infectious diseases in a clinical setting. future trends in  Schwarzmüller, T., F. Istel, C. Bourgeois, W. Glaser, M-M. Houben, T. Gabaldon & K. Kuchler Web: http://funpath.cdl.univie.ac.at/index.php pathogenomics." (2012). Molecular basis and mechanisms implicated in the pathogenicity of the human Publications related to the funded project: fungal pathogen C. glabrata. In preparation  Roetzer, A., C. Gregori, AM, Jennings, J. Quintin, D. Ferrandon, G. Butler, K. Kuchler, G. Ammerer, & C. Schüller (2008). Candida glabrata environmental stress response involves S. cerevisiae Msn2/4 orthologous transcription factors. Mol. Microbiol. 69: 603-620  Hnisz, D., T. Schwarzmüller, & K. Kuchler (2009). Transcriptional loops meet chromatin – a dual layer network controls white-opaque switching in C. albicans. Mol. Microbiol. 74: 1-15  Jacobsen, I.D., S. Brunke, K. Seider, T. Schwarzmüller, C. D’Enfert, K. Kuchler & B. Hube (2010). Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy” Infection & Immunity 78: 1066-1077  Bourgeois, C., O. Majer, I.E. Frohner, L. Tiernay & K. Kuchler (2010). Fungal attacks on |30 31 |

Project name: Exploring Secretion within the bacterial biofilm matrix Acronym: EPS-Matrix Ghigo J.M. (2011) Screening Escherichia coli species biodiversity reveals new biofilm- Coordinator: Jean-Marc GHIGO , Institut Pasteur, Paris, France associated anti-adhesion polysaccharides. mBio 00043-11 Partners: Thierry JOUENNE: Faculté des Dciences de Rouen, Rouen, FranceAlain FILLOUX  Mace, C., , Seyer, D., , Chemni, C., Cosette, P., Di Martino, P., Guery, B., Filloux, A., Fontaine, M., Molle, Imperial Cillege, London, Great BritainInigo LASA University of Navarra, Pampelune, V., Junter, G.A. and T. Jouenne. Identification of biofilm-associated cluster (bac) in Pseudomonas SpainJose PENADES, Instituto Ganadería de Montaña-CSIC, Segorbe, Spain aeruginosa involved in biofilm formation and virulence. Plos One, 2008, 3: 1-10 e3897 Abstract: The development of surface-attached biofilm bacterial communities is commonly  Bernard CS, Bordi C, Termine E, Filloux A, de Bentzmann S. Organization and PprB associated with health and economic problems when colonizing industrial or medical dependent control of the Pseudomonas aeruginosa tad locus involved in Flp pilus surfaces. One of the most characteristic biological features that distinguish from biology. 2009. J. Bacteriol. Mar;191(6):1961-73. planktonic populations is the production of an extracellular matrix embedding the biofilm  Viarre V, Cascales E, Ball G, Michel GP, Filloux A, Voulhoux R. HxcQ liposecretin is self- bacteria. The objective of the EPS-Matrix project was to identify matrix proteins and piloted to the outer membrane by its N-terminal lipid anchor. J. Biol. Chem. 2009 Dec other molecules that could play new biological roles in biofilms formed by Escherichia coli, 4;284(49):33815-23. Salmonella enterica serovar Enterididis, Pseudomonas aeruginosa and Staphylococcus  Garvis S, Munder A, Ball G, de Bentzmann S, Wiehlmann L, Ewbank JJ, Tümmler B, Filloux A. aureus. Soluble molecules potentially accumulating in the matrix of mature biofilms Caenorhabditis elegans semi-automated liquid screen reveals a specialized role for the formed in microfermentors were extracted and analyzed using different approaches chemotaxis gene cheB2 in Pseudomonas aeruginosa virulence. PLoS Pathog. 2009 Aug;5(8). including proteomic analysis as well as different phenotypic assays. In parallel,  Vergara-Irigaray, M., J. Valle, N. Merino, C. Latasa, B. Garcia, I. Ruiz de Los Mozos, C. genomic analysis of potential bacterial secretion systems potentially delivering proteins Solano, A. Toledo-Arana, J. R. Penades & I. Lasa, (2009) Relevant role of fibronectin- within the matrix was used to investigate protein-mediated biofilm development. The binding proteins in Staphylococcus aureus biofilm-associated foreign-body infections. contribution of the identified secreted molecules, as well as their biofilm specificity was Infect Immun 77: 3978-3991. carried out by 5 groups (3 in France, 2 in Spain) with complementary expertise. The scientific  Merino, N., A. Toledo-Arana, M. Vergara-Irigaray, J. Valle, C. Solano, E. Calvo, J. A. Lopez, activity directly derived from this programme led, in particular to the study of S. aureus T. J. Foster, J. R. Penades & I. Lasa, (2009) Protein A-mediated multicellular behavior in proteinaceous-dependent biofilm matrix and the demonstration of the role of LPXTG Staphylococcus aureus. J Bacteriol 191: 832-843. protein and Fibronectin binding proteins in biofilm formation. It also led to the functional  Marti, M., M. P. Trotonda, M. A. Tormo-Mas, M. Vergara-Irigay, A. L. Cheung, I. Lasa & J. R. characterization of a family of 7 chaperone-usher fimbriae previously considered as Penades, (2009) Extracellular proteases inhibit protein-dependent biofilm formation in cryptic. The methodology of biofilm-matrix extraction used in the programme also led to Staphylococcus aureus. Microbes Infect. In press the identification of polysaccharidic polymers produced within the E. coli and P. aeruginosa  Vergara-Irigaray, M., J. Valle, N. Merino, C. Latasa, B. Garcia, I. Ruiz de Los Mozos, C. biofilm matrix. The programme is still in progress regarding functional analysis of the type Solano, A. Toledo-Arana, J. R. Penades & I. Lasa, (2009) Relevant role of fibronectin- 2 and type 6 secretion pathways in E. coli and P. aeruginosa. The biological relevance of the binding proteins in Staphylococcus aureus biofilm-associated foreign-body infections. findings directly derived from the programme and their contribution to the understanding Infect Immun 77: 3978-3991. of the biological role performed by the bacterial biofilm matrix will be discussed .  Merino, N., A. Toledo-Arana, M. Vergara-Irigaray, J. Valle, C. Solano, E. Calvo, J. A. Lopez, Publications related to the funded project: T. J. Foster, J. R. Penades & I. Lasa, (2009) Protein A-mediated multicellular behavior in  Collet, A. ; Cosette, P.; Beloin, C.; Ghigo, J.M.; Rihouey, C.; Lerouge, P.; Junter, G.A. And T. Staphylococcus aureus. J bacteriol 191: 832-843. Jouenne. (2008). Impact of rpoS deletion on the proteome of Escherichia coli grown as  Marti, M., M. P. Trotonda, M. A. Tormo-Mas, M. Vergara-Irigay, A. L. Cheung, I. Lasa & J. R. biofilm. Journal of Proteomic Research 7(11):4659-4669. Penades, (2009) Extracellular proteases inhibit protein-dependent biofilm formation in  Valle, J., Da Re, S., Schmid, S., Skurnik, D., D›Ari, R. and Ghigo, J. M. (2008) The amino acid Staphylococcus aureus. Microbes Infect. In press valine is secreted in continuous-flow bacterial biofilms J Bacteriol.190:264-74.  Kowalska K, Soscia C, Combe H, Vasseur P, Voulhoux R, Filloux A. The C-terminal  Korea, C. G., Badouraly, R., Prevost, M. C., Ghigo, J. M. and Beloin, C. (2010) Escherichia coli amphipathic alpha-helix of Pseudomonas aeruginosa PelC outer membrane protein is K-12 possesses multiple cryptic but functional chaperone-usher fimbriae with distinct required for its function. Biochimie. 2009. surface specificities Environ Microbiol.12:1957-77.  Mikkelsen H, Ball G, Giraud C, Filloux A. 2009 Expression of Pseudomonas aeruginosa  Ferrieres, L., Hemery, G., Nham, T., Guerout, A. M., Mazel, D., Beloin, C. and Ghigo, J. M. CupD fimbrial genes is antagonistically controlled by RcsB and the EAL-containing PvrR (2010) Silent mischief: Mu insertions contaminate products of Escherichia response regulators. PLoS One. Jun 23;4(6):e6018. coli random mutagenesis performed using suicidal transposon delivery Ruer S, Ball G, Filloux A, de Bentzmann S. The ‹P-usher›, a novel protein transporter mobilized by broad-host-range RP4 conjugative machinery J Bacteriol.192:6418-27. involved in fimbrial assembly and TpsA secretion. EMBO J. 2008 Oct 22;27(20):2669-80.  Korea, C. ; J. M. Ghigo and C. Beloin. (2011) The sweet connection: solving the riddle of  Filloux A, Hachani A, Bleves S. The bacterial type VI secretion machine: yet another player multiple sugar-binding fimbrial adhesins in Escherichia coli Biessays . vol. 33 (4) pp. 300-11 for protein transport across membranes. Microbiology. 2008 Jun;154(Pt 6):1570-83.  Rendueles, O. ; Travier, L. ; Latour-Lambert, P. ; Fontaine, T. ; Magnus, J. ; Denamur, E. and |32 33 |

Project name: Glycoshield: Surface Modulation of the Fungal & Host Response using a 2, 308-320 Genomic Approach (Acronym: Glycoshield)  Cantero, P. D. and Ernst, J. F. (2011) Damage to the glycoshield activates PMT-directed Coordinator: Jesús Pla Alonso Address: Dep. Microbiología II, Fac. de Farmacia, O-mannosylation via the Msb2-Cek1 pathway in Candida albicans. Mol. Microbiol. U.Complutense de Madrid, Madrid, Spain. 80:715-725. Partners: Jesús Pla Alonso, Dep. Microbiología II, Facultad de Farmacia, Universidad  Cantero, P. D., Lengsfeld, C., Prill, S. K.-H., Subanović, M., Román, E., Pla, J., and Ernst, Complutense de Madrid, Madrid, Spain J. F. (2007) Transcriptional and physiological adaptation to defective protein-O- Joachim F. Ernst, Institut für Mikrobiologie; Heinrich-Heine-Universität Düsseldorf, mannosylation in Candida albicans. Mol. Microbiol. 64: 1115-1128. Düsseldorf, Germany  Corbucci, C., Cenci, E., Skrzypek, F., Gabrielli, E., Mosci, P., Ernst, J. F., Bistoni, F., and Guilhem JANBON, Unité de Mycologie Moléculaire; Institut Pasteur, Paris, France Vecchiarelli, A. (2007) Immune response to Candida albicans is preserved despite defect Steffen Michael Rupp,Fraunhofer Institut; Lehrstuhl für Grenzflächenverfahrenstechnik, in O-glycosylation of secretory proteins. Med. Mycology 45: 709 – 719. Stuttgart, Germany  Correia,I. et al. (2010) MAPK cell-cycle regulation in Saccharomyces cerevisiae and Daniel Poulain, Faculté de Médecine, Lille Cedex, France Candida albicans. Future. Microbiol. 5, 1125-1141 Angel Dominguez Olavarri, Dep. of Microbiology and Genetics, University of Salamanca,  De Jesus M., Nicola A.M., Rodrigues M.L, Janbon G. & Casadevall A. (2009) Salamanca, Spain Capsular localization of the Cryptococcus neoformans polysaccharide component Claude Gaillardin, Microbiologie et Génétique Moléculaire, Institut National Agronomique galactoxylomannan. Eukaryotic Cell 8, 96-103. Paris-Grignon, Thiverval-Grignon, France  Ernst,J.F. and Pla,J. (2011) Signaling the glycoshield: maintenance of the Candida albicans Abstract: Host-interaction between fungi and the mammalian cells is a largely unexplored cell wall. Int. J. Med. Microbiol. 301, 378-383 area of research, yet essential for the design of novel approaches towards the control  Fradin, C, Slomianny M C, Mille C, Masset A, Sendid B, Ernst J F, Michalski J C, Poulain D. of fungal infections. In this project, the role of the fungal cell wall as modulator of the beta-1,2 oligomannose adhesion epitopes are widely distributed over the four families interaction of pathogenic fungi with the mammalian host has been analysed. The main leit of Candida albicans cell wall mannoproteins and are associated through both N- and motiv of the project is that the surface of fungal pathogens undergoes profound changes O-glycosylation processes. Infect. Immun., 2008, 76:4509-17. as a result of environmental conditions; such modifications are crucial for the generation  Fradin, C., Slomianny, M.C., Mille, C., Masset, A., Sundstrom, P., Ernst, J. F., Michalski, J.C., of the immune response, which is of primary importance in the control of the disease. The and Poulain, D. (2008) -1,2 oligomannose adhesion epitopes are widely distributed over knowledge of such response(s) is important to develop an effective vaccine for several the four families of Candida albicans cell wall mannoproteins and associated through fungal infections. Within this project we have carried out genome wide strategies (proteomic both N- and O-glycosylation processes. Infect. Immun. 76: 4509-4517. and genomic) as well as more conventional methodologies (genetics, biochemistry, flow  Galan-Diez,M. et al. (2010) Candida albicans beta-glucan exposure is controlled by the cytometry) to characterise cell surface alterations in fungal mutants. We have developed fungal CEK1-mediated mitogen-activated protein kinase pathway that modulates and studied knock out mutants in genes that influence surface composition, mainly through immune responses triggered through dectin-1. Infect. Immun. 78, 1426-1436 glycosylation but also some involved in signalling and coding for structural components of  Geunes-Boyer, S. Oliver, T.N. Janbon, G. Lodge J.K., Heitman J., Perfect J.R. & Wright the wall. We have characterized their function in the fungal cell, focusing on their ability to J.R. (2009) Surfactant Protein D increases phagocytosis of hypocapsular Cryptococcus interact with host cells using both in vitro (cell lines) and in vivo methods (virulence assay in neoformans by murine macrophages and enhances fungal survival. Infect. Immun. 77, animal models). The efficacy of some of them as vaccines has been also tested. 2783-2794. Publications related to the funded project:  awhara S, and Poulain D. Saccharomyces boulardii decreases inflammation and intestinal  Alonso-Monge,R. et al. (2009) A host view of the fungal cell wall. In Evolutionary biology colonization by Candida albicans in a mouse model of chemically-induced colitis. Medical of bacterial and fungal pathogens (Baquero Mochales,F.et al. , eds), pp. 105-115, ASM Mycology. 2007. 45: 691-700 Press.  Jawhara S, Thuru X, Standaert-Vitse A, Jouault T, Mordon S, Sendid B, Desreumaux P, and  Alonso-Monge,R. et al. (2009) Fungi sensing environmental stress. Clin. Microbiol. Infect. Poulain D. Colonization of mice by Candida albicans is promoted by chemically- induced 15 Suppl 1, 17-19. colitis and augments inflammatory responses through galectin-3. Journal of Infectious  Alonso-Monge,R. et al. (2009) The Hog1 MAP kinase controls respiratory metabolism in Diseases. 2008, 197(7):972-80. the fungal pathogen Candida albicans. Microbiol. 155, 413-423.  Jouault, T.Jouault, T A. Sarazin, M. Martinez-Esparza, C. Fradin, B Sendid, and D. Poulain.  Anke Burger-Kentischer, Ina S. Abele, Doris Finkelmeier, Karl-Heinz Wiesmüller, Steffen Host responses to a versatile commensal: PAMPs and PRRs interplay leading to Rupp. A new cell-based innate immune receptor assay enables the examination of tolerance or infection by Candida albicans. Cellular Microbiology 2009 11:1007-1015 receptor activity, ligand specificity, signalling pathways and the detection of pyrogens.  Kurtz, D., Szafranski, E., Noffz, C. and Ernst, J. F. (2007) Dual target specificity of the Manuscript submitted. Candida albicans Efg1 regulator. Submitted.  Arana,D.M. et al. (2009) The role of the cell wall in fungal pathogenesis. Microb. Biotechnol. Lengeler, K., Tielker, D., and Ernst, J. F. (2008) Protein-O-mannosyltransferases in |34 35 |

virulence and development. Cell. Mol. Life Sci. 65: 528-544. Project name: Large scale screening of potential key factors involved in the commensalism  Maes E., Mille C., Janbon G., Poulain D. & Guérardel Y. (2009) Molecular phenotyping of / virulence transition of Enterococcus faecalis (Acronym: FaecalVir) -mannosyltransferases deficient Candida albicans cells by High Resolution-Magic Angle Coordinator: Axel Hartke, Lab. Microbiologie de l’Environnement, Université de Caen, Spinning NMR. J. Biochem. 145, 413-419 France  Martinez-Esparza M, Sarazin A, Poulain D, and Jouault T. 2007. A method for examining Partners: Pascale Serror–Ublo/ Jouy en Josas, Institut National de la Recherche Agronomique glycans surface expression of yeasts by flow cytometry. In S. Rupp, K. Sohn, and N. (INRA), France Hauser (ed.), Methods Mol Biol. 2009, 470:85-94. Johannes Huebner, Lab. of Infectious Disease Research, University Hospital Freiburg, Mille C, Bobrowicz P, Trinel P A, Li H, Maes E, Guerardel Y, Fradin C, Martinez- Esparza M, Germany Davidson R C, Janbon G, Poulain D, and Wildt S. Identification of a new family of genes Fatima Lopes, Lab. Stress by Antibiotics and Virulence of Enterococci, IBET, Portugal involved in beta-1,2 mannosylation of glycans in Pichia pastoris and Candida albicans. J. Bruno Gonzales-Zorn, Faculty of Veterinary Science, University Compultense de Madrid, Biol. Chem., 2008, 283:9724-36. Spain  Mille C, Fradin C, Trinel P. A., Delplace, F, Maes E, Guerardel Y, Janbon G, Wildt S, Poulain Abstract: Enterococci are commensals but also important causes of nosocomial infections D. Candida albicans BMT5 and BMT6 genes are involved in beta-mannosylation of that are highly resistant against virtually all clinical antibiotics. To better understand its phospholipomannan. Glycobiology. revised. pathogenicity, a library of targeted insertion in 178 genes has been constructed  Mille C., Trinel P.A., Fradin C., Delplace F., Maes E., Guerardel Y., Wildt S., Janbon G., and screened for their resistance to oxidative stress, antibiotic resistance, virulence in a & Poulain D. (2009) Candida albicans BMT5 and BMT6 genes are involved in beta- surrogate insect model, resistance to opsonophagocytosis and adherence to human colon mannosylation of phospholipomannan. (in revision) carcinoma cells.  Román,E. et al. (2009) Msb2 signaling mucin controls activation of Cek1 mitogen- Several mutants affected in genes encoding cell surface exposed proteins displayed a activated protein kinase in Candida albicans. Eukaryot. Cell 8, 1235-1249 phenotype of reduced virulence in Galleria mellonella. Some mutants affected in glycosyl  Román,E. et al. (2009) The Cek1 MAPK is a short-lived protein regulated by quorum hydrolases and putative transcriptional regulators showed also increased virulence in this sensing in the fungal pathogen Candida albicans. FEMS Yeast Res. 9, 942-955 model. A total of 16 mutations affected phagocytosis and complement susceptibility. Most  Sarazin, A., D. Poulain, and T. Jouault. In vitro pro- and anti-inflammatory responses of these mutants were efficiently killed by a combination of PMNs with complement and to viable Candida albicans yeasts by a murine macrophage cell line. Medical Mycology one mutant was sensitive to complement alone. Several other mutants showed significant Submitted. differences in antibiotic resistance with one mutant hypersensitive to a 3rd generation  Szafranski-Schneider,E. et al. (2012) Msb2 Shedding Protects Candida albicans against cephalosporine. Antimicrobial Peptides. PLoS. Pathog. 8, e1002501 Our study contributed to the deciphering of cellular roles of hitherto unknown-function genes and to a better understanding of E. faecalis virulence and intrinsic resistance to antibiotics which may lead to the identification of additional targets for alternative treatment and prevention options against otherwise untreatable enterococcal infections. Publications related to the funded project:  Theilacker C, Sanchez-Carballo P, Toma I, Fabretti F, Sava I, Kropec A, Holst O, Huebner J. 2009. Glycolipids are involved in biofilm accumulation and prolonged bacteraemia in Enterococcus faecalis. Mol Microbiol 71(4):1055-69.  Le Jeune, A., Torelli, R., Sanguinetti, M., Giard, J.-C., Hartke, A., Auffray Y., and Benachour, A. 2010. SigV, an Extracytoplasmic function sigma factor plays a key role in the original model of lysozyme resistance and in virulence of Enterococcus faecalis. PloSOne 11; 5(3):e9658.  Hanin A, Sava I, Bao Y, Huebner J, Hartke A, Auffray Y, and Sauvageot N. 2010. Screening of in vivo activated genes in Enterococcus faecalis during insect and mouse infections and growth in urine. PLoS One 29; 5(7):e11879.  Zhao, C., Hartke, A., La Sorda, M., Posteraro, B., Laplace, J.-M., Auffray, Y and Sanguinetti, M. 2010. Methionine Sulfoxide Reductases A and B of Enterococcus faecalis: implication in oxidative stress and virulence. Infect. Immun. 78(9): 3889-97.  Le Jeune A, Touchet F, Zhao C, Hartke A, Auffray Y, and Benachour A. 2010. Construction of a New Sensitive Molecular Tool for the Study of Gene Expression in Enterococcus |36 37 |

faecalis. J Mol Microbiol Biotechnol. 19(3):159-168. Project name: European Initiative to Fight Chlamydial Infections by Unbiased Genomics  Michaux, C., Sanguinetti, M., Auffray, Y., Posteraro, B., Gilmore, M.S., Hartke A. and Giard, (Acronym: ECIBUG) J.C. 2010. SlyA is a transcriptional regulator involved in the virulence of Enterococcus Coordinator: Matthias Maass, Institute of Medical Microbiology, Hygiene and Infectious faecalis. Infect. Immun. 79: 2638-2645 Diseases,University Hospital Salzburg, Salzburg,Austria  Rigottier-Gois L., Alberti A., Houel A., Taly JF., Palcy P., Manson J., Pinto D., Matos RC., Partners: Georg Wick, Division of Experimental Pathophysiology and Immunology, Innsbruck Carrilero L., Montero N., Tariq M., Karsens H., Repp C., Kropec A., Budin-Verneuil A., Medical University,Innsbruck, Austria Benachour A., Sauvageot N., Bizzini A., Gilmore MS., Bessières P ., Kok J., Huebner J., Mirja Puolakkainen, Infection Pathogenesis Laboratory,Viral Diseases & Immunology, Lopes F., Gonzalez-Zorn B., Axel Hartke A., and Serror P. 2011. Large-scale screening of a National Public Health Institut, Helsinki, Finland targeted Enterococcus faecalis mutant library identifies envelope and regulatory fitness Pia Vuorela, Drug discovery and development technology center, Division of Pharmacy, Abo factors. PlosOne 6(12): e29023. Academi University, Biocity, Turku, Finland  Michaux C, Martini C, Hanin A, Auffray Y, Hartke A, and Giard JC. 2011. SlyA regulator Agathe Subtil, Unité de Biologie des Interactions Cellulaires, CNRS URA-2582, Institut is involved in bile salts stress response of Enterococcus faecalis. FEMS Microbiol Lett. Pasteur,Paris, France 324:142-6. Jens Gieffers, Medizin. Mikrobiologie & Hygiene Universität Lübeck, Lübeck, Germany  Bao YY., Sakinc T., Laverde D., Wobser D., Benachour A., Theilacker C., Hartke A. and Georg Häcker, Institute for Medical Microbiology, Immunology and Hygiene, Huebner J. 2012. Role of mprF1 and mprF2 in the pathogenicity of Enterococcus faecalis. München, Germany PlosOne (in press). Johannes H. Hegemann, Lehrstuhl für Funktionelle Genomforschung der Mikroorganismen, Heinrich-Heine-Universität, Duesseldorf, Germany Thomas F. Meyer, Max Planck Institute for Infection Biology, Department of Molecular Project name: Systematic analyses of kinase and phosphatase function in morphological, Biology, Berlin, Germany environmental, and virulence responses of the human fungal pathogen Candida albicans Abstract: ECIBUG has integrated nine key laboratories that focus on biology of the (Acronym:KinCan) intracellular pathogen Chlamydia. Integrating the multicompetence of the consortial Coordinator: Robert Arkowitz, CNRS/INSERM/University of Nice, FRANCE members in the field of bacterial and host genomics, proteomics, transcriptomics, signal Partners: Joachim Morschhäuser, Universität Würzburg, Germany transduction, drug design, and infection models should pose a major advantage in fighting Daniel Kornitzer, Technion – Israel Institute of Technology, Israel one of the most frequent human pathogen groups. C. trachomatis is the leading cause Abstract: Candida albicans, normally harmless commensal on mucosal surfaces, is also for sexually transmitted disease and preventable infectious blindness. C. pneumoniae is a the most prevalent etiological agent of life-threatening systemic fungal infections in worldwide cause of community-acquired pneumonia and may predispose to arteriosclerosis. immunocompromised individuals. C. albicans’s success as a pathogen is thought to result Depending on the environmental conditions chlamydiae enter a reproductive cycle or a from its ability to switch between different morphological states and to adapt to the various non-replicative state of persistence that leads to treatment-refractory chronic infection. challenges of the human host. These adaptive capacities require signal transduction The consortium produced novel genomic data to better understand the pathobiology of pathways that relay external signals to adaptive cellular mechanisms. Protein kinases chlamydial infection on a genomic level which include: Identification of C. pneumoniae domains are the most abundant domains in yeast and these proteins are one of the most effector proteins with type III secretion signals in two complementary high-throughput important enzyme families. We have constructed a comprehensive set of C. albicans screening approaches, identificatiion of 59 proteins that may alter infectivity in a siRNA strains in which all of the protein kinases and phosphatases are overexpressed from an loss of function screen for C. trachomatis, an In-depth analysis of postinfectiously modified inducible promoter. We have monitored cellular responses and survival under a wide range human signaling cascades and chlamydial interaction partners, definition of 7 novel of conditions for each of the ~180 overexpression strains. From these screens individual synthetic and 9 novel natural antichlamydial compounds.ECIBUG created the scientific kinases or phosphatases have been identified that are specific for unique adaptive base for a follow-up ERA-NET PathoGenoMics consortium: ChlamyTrans. responses. Candidate genes have been studied further by molecular genetic techniques Publications related to the funded project: to determine the specific role of these identified regulators in detail. These studies will  Bunk S, Suznea I, Rupp J, Summersgill JT, Maass M, Schrattenholz A, Wendel A, Przybylski ultimately results in a better understanding of regulatory and adaptive pathways and lead M, Hermann C. Immunoproteomic identification of novel Chlamydia pneumoniae to novel ways to inhibit C. albicans growth and pathogenicity. antigens enables serological determination of persistent Chlamydia pneumoniae infections. Journal of Immunology 2008;180:5490-8  Rattei T, Ott S, Gutacker M, Rupp J, Maass M, Schreiber S, Solbach W, Gieffers J. Diversity of the Obligate Intracellular Bacterium Chlamydia pneumoniae by Genome-Wide Analysis of Single Nucleotide Polymorphisms: Evidence for Highly Clonal Population Structure. BMC Genomics 2007;8:355 |38 39 |

 Kern JM, Maass V, Rupp J, Maass M. Proliferative stimulation of the vascular Endothelin-1 2 cells. J. Bacteriology 2008;190:3757-3767 axis in vitro and ex vivo by infection with Chlamydia pneumoniae. Thromb Haemost.  Ying S, Christian JG, Paschen SA, Häcker G. can protect host cells 2009;102:743-53. against apoptosis in the absence of cellular Inhibitor of Apoptosis Proteins and Mcl-1.  Salin O, Alakurtti S, Pohjala L, Siiskonen A, Maass V, Maass M, Yli-Kauhaluoma J, Microbes Infect 2008;10:97- 101 Vuorela P. Inhibitory effect of the natural product betulin and its derivatives against the  Ying S, Pettengill M, Latham ER, Walch A, Ojcius DM, Häcker G. Premature apoptosis intracellular bacterium Chlamydia pneumoniae. Biochem Pharmacol. 2010;80:1141-51. of Chlamydia-infected cells disrupts chlamydial development. J Infect Dis  Keurulainen L, Salin O, Siiskonen A, Kern JM, Alvesalo J, Kiuru P, Maass M, 2008;198:1536-44. Yli-Kauhaluoma J, Vuorela P. Design and Synthesis of 2-Arylbenzimidazoles and  Paschen S, Christian JG., Vier J, Schmidt F, Walch A, Ojcius DM, Häcker G. Evaluation of Their Inhibitory Effect against Chlamydia pneumoniae. J Med Chem. Cytopathicity of Chlamydia infection can be largely reproduced by expressing a single 2010;53:7664-74. chlamydial gene, Chlamydial Protease-like Activity Factor. J Cell Biol 2008; 182:117-27  Kern J, Maass V, Maass M. Molecular pathogenesis of chronic Chlamydia pneumoniae infection: a brief overview. Clin Microbiol Infection 2009; 15:16-31  Kern J, Maass V, Maass M. Chlamydia pneumoniae-induced pathological signaling in the vasculature. FEMS Immunol Med Microbiol: 2009; 55:131-139  Kern JM, Maass V, Maass M. Chlamydia pneumoniae adversely modulates vascular cell Pneumocystis: Revealing the shift from fungal colonization to lung disease properties by direct interaction with signalling cascades. Thromb Haemost. 2009 102: Coordinator: Eduardo Dei-Cas, FR 1064-1070 Partners: Enrique F. Calderón, ES  Penttilä T, Haveri A, Tammiruusu A, Vuola JM, Lahesmaa R, Puolakkainen M. Enhanced Melanie T. Cushion, USA clearance but severe inflammation during pulmonary Chlamydia pneumoniae infection Abstract: The Pneumocystis group, composed of three research teams from three countries, in IL-10 knockout mice. Microbial Pathogenesis 2008; 45:2529 is aiming to determine the biological changes undergone by the organisms, that allows  Oksaharju A, Lappalainen J, Puolakkainen M, Pussinen PJ, Kovanen PT, Lindstedt KA. extensive proliferation of the fungus in the lungs of susceptibile hosts. This culminates Proatherogenic bacteria induce an inflammatory response in cultured mast cells. J Cell in severe pneumonitis and, ultimately, in respiratory failure. By targeting Pneumocystis Mol Med 2009;13:103-113 jirovecii, which is often detected in human pulmonary disease, the scientists hope to  Palikhe A, Tiirola T, Puolakkainen M, Nieminen MS, Saikku P, Leinonen M, Sinisalo J. generate efficient models for continuous monitoring of infection mechanisms. Chlamydia pneumoniae DNA is present in peripheral blood mononuclear cells during acute coronary syndrome and correlates with chlamydial lipopolysaccharide levels in serum. Scand J Infect Dis. 2009;41:201-5.  Kyläniemi M, Haveri A, Vuola J, Puolakkainen M, Lahesmaa R. Gene expression signatures characterizing the development of lymphocyte response during experimental Chlamydia pneumoniae infection. Microbial Pathogenesis 2009;46:235-42  Puolakkainen M. Innate immunity and Chlamydia pneumoniae vaccines. In: Christiansen G (ed) Proceedings Sixth Meeting of the Society for European Chlamydia Research, pp 67-73, 2008. ISBN 978-87-984259-3-9.  Puolakkainen M. Innate immunity and vaccines in chlamydial infection with special emphasis on Chlamydia pneumoniae. FEMS Immunol Med Microbiol 2009; 55: 167-177  Savijoki K, Alvesalo J, Vuorela P, Leinonen M, Kalkkinen N. Proteomic analysis of Chlamydia pneumoniae –infected HL cells reveals extensive degradation of cytoskeletal proteins. FEMS Immunol Med Microbiol 2009; 54: 375–384  Delevoye C, Nilges M, Dehoux P, Paumet F, Perrinet S, Dautry-Varsat A and A. Subtil. SNARE protein mimicry by an intracellular bacterium. PLoS Pathog 2008; 4(3): e1000022  Rupp J, Solbach W, Gieffers J. Variation in the frequency determining quinolone resistance in Chlamydia trachomatis serovars L2 and D. J Antimicrob Chemother 2008;61:91-94  Wuppermann, FN, Mölleken, K, Julien, M, Jantos, CA and Hegemann, JH. Chlamydia pneumoniae GroEL1 protein is cell surface-associated and required for infection of HEp- |40 41 |

Project name: A comparative molecular analysis of GAS and GBS pathogenesis (Acronym: HEp-2 epithelial cells. ISME J 1:678-692. PathoStrep)  Koller, T., A. G. Manetti, B. Kreikemeyer, C. Lembke, I. Margarit, G. Grandi, and A. Podbielski. Coordinator: Patrick Trieu-Cuot,Institut Pasteur, France 2010. Typing of the pilus-protein-encoding FCT region and biofilm formation as novel Partners: Philipe Glaser, Institut Pasteur, France parameters in epidemiological investigations of Streptococcus pyogenes isolates from Bernd Kreikemeyer/ Andreas Podbielski, University Rostock, Germany various infection sites. J Med Microbiol 59:442-452. Emanuel Hanski, The Hebrew University Hadassah Medical School, Israel  Koller, T., D. Nelson, M. Nakata, M. Kreutzer, V. A. Fischetti, M. O. Glocker, A. Podbielski, Richard Muench, Technical University Braunschweig, Germany and B. Kreikemeyer. 2008. PlyC, a novel bacteriophage lysin for compartment-dependent Abstract: Group A and B streptococci (Streptococcus pyogenes (GAS) and Streptococcus proteomics of Group A Streptococci. Proteomics 8:140-148. agalactiae (GBS), respectively) produce approximately one third of all human bacterial  Konto-Ghiorghi, Y., E. Mairey, A. Mallet, G. Dumenil, E. Caliot, P. Trieu-Cuot, and S. infections. In this project, automated high-throughput methods were used to screen GAS Dramsi. 2009. Dual role for pilus in adherence to epithelial cells and biofilm formation in and GBS random and targeted libraries of mutants with altered expression of surface . PLoS Pathog 5:e1000422. components (e.g., proteins, capsule, and lipoteichoic acids) and to identify novel virulence  Kreikemeyer, B., M. Nakata, T. Koller, H. Hildisch, V. Kourakos, K. Standar, S. Kawabata, factors including regulators. The contribution of these factors to pathogenesis were M. O. Glocker, and A. Podbielski. 2007. The Streptococcus pyogenes serotype M49 Nra- evaluated by studying interaction of the corresponding mutants with phagocytic and non Ralp3 transcriptional regulatory network and its control of virulence factor expression phagocytic cell lines, as well as by using animal models. We also carried out extensive from the novel eno ralp3 epf sagA pathogenicity region. Infect Immun 75:5698-5710. analysis of the regulatory networks responsible for the production of the newly discovered  Mistou, M. Y., S. Dramsi, S. Brega, C. Poyart, and P. Trieu-Cuot. 2009. Molecular dissection and known virulence factors. This was accomplished by using the entire gamut of genome- of the secA2 locus of Group B Streptococcus reveals that glycosylation of the Srr1 LPXTG wide global analyses: transcriptome, proteome, and secretome and by using and developing protein is required for full virulence. J Bacteriol 191:4195-4206. new tools for analyses of the generated data. Our results have contributed  Nakata, M., T. Koller, K. Moritz, D. Ribardo, L. Jonas, K. S. McIver, T. Sumitomo, Y. Terao, S. to a better understanding of how the closely related species S. pyogenes and S. agalactiae Kawabata, A. Podbielski, and B. Kreikemeyer. 2009. Mode of expression and functional became such successful human pathogens. characterization of FCT-3 pilus region-encoded proteins in Streptococcus pyogenes Publications related to the funded project: serotype M49. Infect Immun 77:32-44.  Belotserkovsky, I., M. Baruch, A. Peer, E. Dov, M. Ravins, I. Mishalian, M. Persky, Y. Smith,  Oliveira, L., P. Madureira, E. B. Andrade, A. Bouaboud, E. Morello, P. Ferreira, C. Poyart, and E. Hanski. 2009. Functional analysis of the quorum-sensing streptococcal invasion P. Trieu-Cuot, and S. Dramsi. 2012. Group B Streptococcus GAPDH is released upon cell locus (sil). PLoS Pathog 5:e1000651. lysis, associates with bacterial surface, and induces apoptosis in murine macrophages.  Courtney, H. S., I. Ofek, T. Penfound, V. Nizet, M. A. Pence, B. Kreikemeyer, A. Podbielski, PLoS One 7:e29963. D. L. Hasty, and J. B. Dale. 2009. Relationship between expression of the family of M  Panchaud, A., L. Guy, F. Collyn, M. Haenni, M. Nakata, A. Podbielski, P. Moreillon, and C. A. proteins and lipoteichoic acid to hydrophobicity and biofilm formation in Streptococcus Roten. 2009. M-protein and other intrinsic virulence factors of Streptococcus pyogenes pyogenes. PLoS One 4:e4166. are encoded on an ancient pathogenicity island. BMC Genomics 10:198.  Dramsi, S., S. Dubrac, Y. Konto-Ghiorghi, V. Da Cunha, E. Couve, P. Glaser, E. Caliot, M.  Papasergi, S., S. Brega, M. Y. Mistou, A. Firon, V. Oxaran, R. Dover, G. Teti, Y. Shai, P. Trieu- Debarbouille, S. Bellais, P. Trieu-Cuot, and M. Y. Mistou. 2012. Rga, a RofA-Like Regulator, Cuot, and S. Dramsi. 2011. The GBS PI-2a pilus is required for virulence in mice neonates. Is the Major Transcriptional Activator of the PI-2a Pilus in Streptococcus agalactiae. PLoS One 6:e18747. Microb Drug Resist. DOI:10.1089/mdr.2012. 0005  Sugareva, V., R. Arlt, T. Fiedler, C. Riani, A. Podbielski, and B. Kreikemeyer. 2010. Serotype-  Fiedler, T., B. Kreikemeyer, V. Sugareva, S. Redanz, R. Arlt, K. Standar, and A. Podbielski. and strain- dependent contribution of the sensor kinase CovS of the CovRS two- 2010. Impact of the Streptococcus pyogenes Mga regulator on human matrix protein component system to Streptococcus pyogenes pathogenesis. BMC Microbiol 10:34. binding and interaction with eukaryotic cells. Int J Med Microbiol 300:248-258.  Wood, D. N., K. E. Weinstein, A. Podbielski, B. Kreikemeyer, J. P. Gaughan, S. Valentine,  Henneke, P., S. Dramsi, G. Mancuso, K. Chraibi, E. Pellegrini, C. Theilacker, J. Hubner, S. and B. A. Buttaro. 2009. Generation of metabolically diverse strains of Streptococcus Santos-Sierra, G. Teti, D. T. Golenbock, C. Poyart, and P. Trieu-Cuot. 2008. Lipoproteins pyogenes during survival in stationary phase. J Bacteriol 191:6242-6252. are critical TLR2 activating toxins in group B streptococcal sepsis. J Immunol 180:6149-6158.  Klein, J., S. Leupold, R. Munch, C. Pommerenke, T. Johl, U. Karst, L. Jansch, D. Jahn, and I. Retter. 2008. ProdoNet: identification and visualization of prokaryotic gene regulatory and metabolic networks. Nucleic Acids Res 36:W460-464.  Klenk, M., M. Nakata, A. Podbielski, B. Skupin, H. Schroten, and B. Kreikemeyer. 2007. Streptococcus pyogenes serotype-dependent and independent changes in infected |42 43 |

Project name: Deciphering the interface of commensal and extraintestinal pathogenic E. Coli therapeutic and preventive strategies (e.g. new targets for antibiotics and new vaccine (Acronym: ExPEC) candidates) in human and veterinary medicine. Coordinator: Jörg Hacker, German Academy of Sciences Leopoldina / Ulrich Dobrindt, Publications related to the funded project: University of Münster, Institute of Hygiene, Germany  Bielaszewska, M., Dobrindt, U., Gartner, J., Gallitz, I., Hacker, J., Karch, H., Müller, D., Schubert, Partners: Jürgen Heesemann / Sören Schubert, Ludwig-Maximilians University Munich, S., Alexander, S. M., Sorsa, L. J., and Zdziarski, J. 2007. Aspects of genome plasticity in Max-von Pettenkofer Institute, Germany pathogenic Escherichia coli. Int J Med Microbiol 297(7-8):625-639. M. Alexander Schmidt / Helge Karch, Westfälische Wilhelms-Universität Münster, Institute  Homburg S, Oswald E, Hacker J, Dobrindt U. (2007) Expression analysis of the colibactin of Infectiology / Institute of Hygiene, Germany gene cluster coding for a novel polyketide in Escherichia coli. FEMS Microbiol Lett. Chantal Le Bouguénec, Institut Pasteur Paris, Unité de Pathogénie Bactérienne des 275(2):255-262. Muqueuses, France  Barl T, Dobrindt U, Yu X, Katcoff DJ, Sompolinsky D, Bonacorsi S, Hacker J, Bachmann TT. Maryvonne Moulin-Schouleur / Philippe Gilot, Institut National de la Recherche (2008) Genotyping DNA chip for the simultaneous assessment of antibiotic resistance Agronomique, INRA- Centre de Tours Research Unit 1282 - Laboratory of Bacterial and pathogenic potential of extraintestinal pathogenic Escherichia coli. Int J Antimicrob Pathogenicity, France Agents. 32(3):272-277. Eric Oswald, Institut National de la Recherche Agronomique (UMR1225 INRA-ENVT  Bielaszewska M, Middendorf B, Köck R, Friedrich AW, Fruth A, Karch H, Schmidt MA, Toulouse, France) Mellmann A. (2008) Shiga toxin-negative attaching and effacing Escherichia coli: distinct Benita Westerlund-Wikström, University of Helsinki, Department of Biological and clinical associations with bacterial phylogeny and virulence traits and inferred in-host Environmental Sciences, General Microbiology, Finland pathogen evolution. Clin Infect Dis. 47(2):208-217. Levente Emődy, University Medical School – University of Pécs, Department of Medical  Chanteloup NK, Porcheron G, Delaleu B, Germon P, Schouler C, Moulin-Schouleur M, Microbiology and Immunology, Hungary & István Wittmann, University of Pécs, Department Gilot P. (2008) The extra-intestinal avian pathogenic Escherichia coli strain BEN2908 of Medicine and Nephrology, Hungary invades avian and human epithelial cells and survives intracellularly. Vet Microbiol. Béla Nagy / Istvan Tóth, Veterinary Medical Research Institute of the Hungarian Academy 147(3-4):435-439. of Sciences, Hungary  Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, Stappert D, Wantia N, Rodriguez Eliora Z. Ron, Tel Aviv University, Department of Molecular Microbiology and N, Wagner H, Svanborg C, Miethke T. (2008) Subversion of Toll-like receptor signaling by Biotechnology, Israel a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Till T. Bachmann, University of Edinburgh Medical School, Division of Pathway Medicine, Med 14:399-406. United Kingdom  Cortes MA, Gibon J, Chanteloup NK, Moulin-Schouleur M, Gilot P, Germon P. (2008) Bernt Eric Uhlin / Sun Nyunt Wai, Umeå University, Department of Molecular Biology, Inactivation of ibeA and ibeT results in decreased expression of type 1 fimbriae Sweden [associated] in extraintestinal pathogenic Escherichia coli strain BEN2908. Infect Immun. Catharina Svanborg and Björn Wullt, Lund University, Section of Microbiology, Immunology 76(9):4129-4136. and Glycobiology, Sweden [associated]  Dobrindt U, Hacker J. (2008) Targeting virulence traits: potential strategies to combat Abstract: E.coli causing extraintestinal diseases (ExPEC – Extraintestinal Pathogenic E extraintestinal pathogenic E. coli infections. Curr Opin Microbiol. 11(5):409-413. coli) are the major source of urinary tract infections (UTI), and sepsis/bacteremia. ExPEC  Johnson JR, Johnston B, Kuskowski MA, Nougayrede JP, Oswald E. (2008) Molecular are the predominant causes of death from infectious diseases among the elderly as well epidemiology and phylogenetic distribution of the Escherichia coli pks genomic island. J as people with deficient immune response due to malignant diseases, chemotherapy, or Clin Microbiol. 46(12):3906-3911. immunosuppressive diseases. They are also an important factor in newborn meningitis  Mellmann A, Bielaszewska M, Köck R, Friedrich AW, Fruth A, Middendorf B, Harmsen (NBM). Since ExPEC strains associated with human and animal diseases are remarkably D, Schmidt MA, Karch H. (2008) Analysis of collection of hemolytic uremic syndrome- diverse, obvious treatments, including standard vaccination procedures, are unrealistic. The associated enterohemorrhagic Escherichia coli. Emerg Infect Dis. 14(8):1287-1290. ability of ExPEC to accumulate and express multiple virulence-associated determinants  Nagy G, Emődy L, Pál T. (2008) Strategies for the development of vaccines conferring increases their fitness and adaptability and determines their potential to cause disease. broad-spectrum protection. Int J Med Microbiol. 298(5-6):379-395. Several fitness determinants are shared between ExPEC and commensal strains. These  Zdziarski J, Svanborg C, Wullt B, Hacker J, Dobrindt U. (2008) Molecular basis of ExPEC virulence factors enable the pathogens to exploit their hosts in ways unavailable to commensalism in the urinary tract: low virulence or virulence attenuation? Infect Immun. commensal strains, in addition to their role in disease processes, and thus to spread and to 76(2):695-703. persist in the bacterial community. The scientific objective of this project is to understand  Bielaszewska M, Prager R, Vandivinit L, Müsken A, Mellmann A, Holt NJ, Tarr PI, the molecular and epidemiological basis for controlling ExPEC infections and to use the Karch H, Zhang W. (2009) Detection and characterization of the fimbrial sfp cluster in knowledge for the improvement of diagnostic approaches and the development of new enterohemorrhagic Escherichia coli O165:H25/NM isolates from humans and cattle. |44 45 |

Appl Environ Microbiol. 75(1):64-71. effects and interactions of endogenous and horizontally acquired H-NS-like proteins in  Buss C, Müller D, Rüter C, Heusipp G, Schmidt MA. (2009) Identification and characterization pathogenic Escherichia coli. Mol Microbiol. 75(2):280-293. of Ibe, a novel type III effector protein of A/E pathogens targeting human IQGAP1. Cell  Zdziarski J, Brzuszkiewicz E, Wullt B, Liesegang H, Biran D, Voigt B, Grönberg-Hernandez J, Microbiol. 11(4):661-677. Ragnarsdottir B, Hecker M, Ron EZ, Daniel R, Gottschalk G, Hacker J, Svanborg C, Dobrindt  Pichon C, Héchard C, du Merle L, Chaudray C, Bonne I, Guadagnini S, Vandewalle A, Le U. (2010) Host imprints on bacterial genomes - rapid, divergent evolution in individual Bouguénec C. (2009) Uropathogenic Escherichia coli AL511 requires flagellum to enter patients. PLoS Pathog. 6(8):e1001078. renal collecting duct cells. Cell Microbiol. 11(4):616-628.  Krieger JN, Dobrindt U, Riley DE, Oswald E. (2011) Acute Escherichia coli prostatitis in  Putze J, Hennequin C, Nougayrède JP, Zhang W, Homburg S, Karch H, Bringer MA, Fayolle previously health young men: bacterial virulence factors, antimicrobial resistance, and C, Carniel E, Rabsch W, Oelschlaeger TA, Oswald E, Forestier C, Hacker J, Dobrindt U. (2009) clinical outcomes. Urology. 77(6):1420-1425. Genetic structure and distribution of the colibactin genomic island among members of Le Bouguénec C, Schouler C. (2011) Sugar metabolism, an additional virulence factor in the family Enterobacteriaceae. Infect Immun. 77(11):4696-4703. enterobacteria. Int J Med Microbiol. 301(1):1-6.  Rouquet G, Porcheron G, Barra C, Répérant M, Chanteloup NK, Schouler C, Gilot P. (2009) A  Porcheron G, Kut E, Canepa S, Maurel MC, Schouler C. (2011) Regulation of metabolic operon in extraintestinal pathogenic Escherichia coli promotes fitness under fructooligosaccharide metabolism in an extra-intestinal pathogenic Escherichia coli stressful conditions and invasion of eukaryotic cells. J Bacteriol. 191(13):4427-4440. strain. Mol Microbiol. 81(3):717-733.  Schouler C, Taki A, Chouikha I, Moulin-Schouleur M, Gilot P. (2009) A genomic island  Répérant M, Porcheron G, Rouquet G, Gilot P. (2011) The yicJI metabolic operon of of an extraintestinal pathogenic Escherichia coli Strain enables the metabolism Escherichia coli is involved in bacterial fitness. FEMS Microbiol Lett. 319(2):180-186. of fructooligosaccharides, which improves intestinal colonization. J Bacteriol.  Schneider G, Dobrindt U, Middendorf B, Hochhut B, Szijártó V, Emődy L, Hacker J. 191(1):388-393. (2011) Mobilisation and remobilisation of a large archetypal pathogenicity island of  Schubert S, Darlu P, Clermont O, Wieser A, Magistro G, Hoffmann C, Weinert K, Tenaillon uropathogenic Escherichia coli in vitro support the role of conjugation for horizontal O, Matic I, Denamur E. (2009) Role of intraspecies recombination in the spread of transfer of genomic islands. BMC Microbiol. 11:210. pathogenicity islands within the Escherichia coli species. PLoS Pathog. 5(1):e1000257.  Lehti TA, Bauchart P, Dobrindt U, Korhonen TK, Westerlund-Wikström B. (2012) The  Sjöström AE, Balsalobre C, Emődy L, Westerlund-Wikström B, Hacker J, Uhlin BE. (2009) fimbriae activator MatA switches off motility in Escherichia coli by repression of the The SfaXII protein from newborn meningitis E. coli is involved in regulation of motility flagellar master operon flhDC. Microbiology. Mar 15. [Epub ahead of print] and type 1 fimbriae expression. Microb Pathog. 46(5):243-252.  Martinez-Jéhanne V, Pichon C, du Merle L, Poupel O, Cayet N, Bouchier C, Le Bouguénec  Sjöström AE, Sondén B, Müller C, Rydström A, Dobrindt U, Wai SN, Uhlin BE. (2009) C. (2012) Role of the Vpe carbohydrate permease in Escherichia coli urovirulence and Analysis of the sfaX(II) locus in the Escherichia coli meningitis isolate IHE3034 reveals fitness in vivo. Infect. Immun. doi: 10.1128/IAI.00457-12 two novel regulatory genes within the promoter-distal region of the main S fimbrial  Pichon C, du Merle L, Caliot ME, Trieu-Cuot P, Le Bouguénec C. (2012) An in silico model for operon. Microb Pathog. 46(3):150-155. identification of small RNAs in whole bacterial genomes: characterization of antisense  Tóth I, Nougayrède JP, Dobrindt U, Ledger TN, Boury M, Morabito S, Fujiwara T, Sugai RNAs in pathogenic Escherichia coli and Streptococcus agalactiae strains. Nucleic Acids M, Hacker J, Oswald E. 2009. Cytolethal distending toxin type I and type IV genes are Res. 40(7):2846-2861. framed with lambdoid genes in extraintestinal pathogenic Escherichia coli.  Porcheron G, Chanteloup NK, Trotereau A, Brée A, Schouler C. (2012) Effect of Infect Immun. 77:492-500. Fructooligosaccharide Metabolism on Chicken Colonization by an Extra-Intestinal  Tóth I., Dobrindt U., Koscsó B., Kósa A., Herpay M., Nagy B. (2012) Genetic and phylogenetic Pathogenic Escherichia coli Strain. PLoS One. 7(4):e35475. analysis of avian extraintestinal and intestinal Escherichia coli. Acta Microbiologica et Immunologica Hungarica. 59., (3) 393-409.  Bauchart P, Germon P, Brée A, Oswald E, Hacker J, Dobrindt U. (2010) Pathogenomic comparison of human extraintestinal and avian pathogenic Escherichia coli - search for factors involved in host specificity or zoonotic potential. Microb Pathog. 49(3):105-115.  Castelain M, Sjöström AE, Fällman E, Uhlin BE, Andersson M. (2010) Unfolding and refolding properties of S pili on extraintestinal pathogenic Escherichia coli. Eur Biophys J. 39(8):1105-1115.  Lehti TA, Bauchart P, Heikkinen J, Hacker J, Korhonen TK, Dobrindt U, Westerlund- Wikström B. (2010) Mat fimbriae promote biofilm formation by meningitis-associated Escherichia coli. Microbiology 156(Pt 8):2408-2417.  Müller CM, Schneider G, Dobrindt U, Emődy L, Hacker J, Uhlin BE. (2010) Differential |46 47 |

Project name:RNAi-Net: Functional analysis of the human mechanisms of human infectious disease, thus assisting the identification of novel drug genome during bacterial infections (Acronym: RNAi-Net) targets for anti-infective therapies. Ultimately, with support from the German BMBF, a Coordinator: Thomas F. Meyer, Max Planck Society for the Advancement of Science, Max BSL3 robotic screening unit was implemented and successfully employed for loss-of- Planck Institute for Infection Biology, Berlin, Germany function (RNAi) screens with high-risk pathogens. Partners: Matthias Maass, University Hospital Salzburg, Institute of Medical Microbiology, Publications related to the funded project: Hygiene and Infectious Diseases, Austria Assay development and integration of thematic areas Mikael Skurnik, University of Helsinki, Haartman Institute, Department of Bacteriology and  Bartfeld S, Engels C, Bauer B, Aurass P, Flieger A, Brüggemann H, Meyer TF. (2009) Immunology, Finland Temporal resolution of two-tracked NF-kappaB activation by Legionella pneumophila. Pascale Cossart, Institut Pasteur, Unité des Interactions Bactéries-Cellules INSERM U604, Cell Microbiol. 11(11):1638-51. INRA USC2020, France  Bartfeld S, Hess S, Bauer B, Machuy N, Ogilvie LA, Schuchhardt J, Meyer TF. (2010) High- David O›Callaghan, INSERM U1047, UFR Medecine, Nimes, France throughput and single-cell imaging of NF- B oscillations using monoclonal cell lines. Martin Aepfelbacher, Universitätsklinikum Hamburg-Eppendorf, Institut für Medizinische BMC Cell Biol. Mar 16;11:21. Mikrobiologie, Virologie und Hygiene, Germany  Mills E, Baruch K, Charpentier X, Kobi S, Rosenshine I. (2008) Real-time analysis of Ingo B. Autenrieth, Eberhard-Karls-Universität Tübingen, Institute for Medical Microbiology effector translocation by the type III secretion system of enteropathogenic Escherichia and Hygiene , Germany coli. Cell Host Microbe. 3(2):104-13. Ilan Rosenshine, The Hebrew University of Jerusalem, Faculty of Medicine, Israel  Shifrin Y, Peleg A, Ilan O, Nadler C, Kobi S, Baruch K, Yerushalmi G, Berdichevsky T, Céu Figueiredo, Institute of Molecular Pathology and Immunology of the University of Altuvia S, Elgrably-Weiss M, Abe C, Knutton S, Sasakawa C, Ritchie JM, Waldor MK, Porto, Porto, Portugal Rosenshine I. (2008) Transient shielding of intimin and the type III secretion system José Antonio Bengoechea, Fundación Caubet-Cimera Illes Balears, Recinte Hospital Joan of enterohemorrhagic and enteropathogenic Escherichia coli by a group 4 capsule. J March, Spain Bacteriol. 190(14):5063-74. Francisco García-del Portillo, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid,  Yerushalmi G, Nadler C, Berdichevski T, Rosenshine I. (2008) Mutational analysis of the Spain locus of enterocyte effacement-encoded regulator (Ler) of enteropathogenic Escherichia Jean-Pierre Gorvel, Centre d›Immunologie de Marseille-Luminy, Marseille, coli. J Bacteriol. 190(23):7808-18. France (associated)  Nadler C, Baruch K, Kobi S, Mills E, Haviv G, Farago M, Alkalay I, Bartfeld S, Meyer TF, Didier Raoult, Université de la Méditerranée, Unité des Rickettsies et pathogènes émergents, Ben-Neriah Y and Rosenshine I. (2010) The Type III secretion effector NleE inhibits NF-B France (associated) activation. PLoS Pathog. 6(1):e1000743. Philippe Sansonetti, Institut Pasteur, Unité de Pathogenie Microbienne Moleculaire, France  Oliveira MJ, Costa AM, Costa AC, Ferreira RM, Sampaio P, Machado JC, Seruca R, Mareel (associated) M, Figueiredo C. (2009) CagA associates with c-met, E-cadherin, and p120-catenin in Jürgen Heesemann, LMU München, Max-von-Pettenkofer-Institut für Hygiene und a multiproteic complex that suppresses Helicobacter pylori-induced cell invasive Medizinische Mikrobiologie, Germany (associated) phenotype. Journal of Infectious Diseases 200:745-55. Michael Hensel, Universitätsklinikum Erlangen, Institut für Klinische Mikrobiologie,  Leite M, Figueiredo C. (2012) A method for short-term culture of human gastric epithelial Immunologie und Hygiene, Germany (associated) cells to study the effects of Helicobacter pylori. In: Helicobacter Species. Methods and Abstract: Research in the RNAi-Net project focused on four major areas – namely, the Protocols, Houghton J (Ed.). Methods in Molecular Biology, Vol. 921. elucidation of (1) innate cellular responses induced by bacteria; (2) host-cell factors  Regueiro V, Moranta D, Campos MA, Margareto J, Garmendia J, Bengoechea JA (2009). important for pathogen replication; (3) morphological or physiological alterations of host Klebsiella pneumoniae increases the levels of Toll-like receptors 2 and 4 in human cells during infection and (4) the modulation of host-immune responses. The MPIIB served airway epithelial cells. Infection and Immunity. 77(2):714-24. as a central competence and training platform in this endeavour, which aimed to uncover  Moranta D, Regueiro V, March C, Llobet E, Margareto J, Larrarte E, Garmendia J, Bengoechea the function of host determinants in microbial infections. Besides the identification of JA. (2010) Klebsiella pneumoniae capsule polysaccharide impedes the expression of- host factors involved in pathogen propagation, unique cellular assays were established defensins by airway epithelial cells. Infection and Immunity. 78:1135-1146. that allowed quantitative assessment of critical signalling pathways such as the NF-kB  Frank C, Bengoechea JA. (2010) Functional genomics to identify therapeutic prohylactic pathway, which regulates host-cell inflammatory responses. Moreover, as a paradigm targets. Environmental Microbiology Reports. 2(2):219–227. of host-cell dependent infection, the influenza model was used, which identified  Reguerio V, Moranta D, Frank CG, Margareto J, Larrarte E, Garmendia J, Bengoechea JA. hundreds of essential host-cell determinants in a genome-wide screen. Thus, RNAi-Net (2011) Klebsiella pneumoniae subverts the activation of inflammatory responses in a not only succeeded in the implementation of a new concept in infectious disease research NOD1-dependent manner. Cellular Microbiology. 13:135-153. within the European community, but also generated novel insights into the cellular  March C, Moranta D, Regueiro V, Llobet E, Tomás A, Garmendia J, Bengoechea JA. (2011) |48 49 |

Klebsiella pneumoniae outer membrane protein A is required to prevent the activation Project name: Spatio-temporal analysis of Listeria-host protein interactions of airway epithelial cells. Journal Biological Chemistry. 286:9956-9967 (Acronym: SPATELIS)  Frank CG, Reguerio V, Rother M, Moranta D, Maeurer AP, Garmendia J, Meyer TF, Coordinator: Trinad Chakraborty, Justus-Liebig University, Institute of Medical Microbiology, Bengoechea JA. Klebsiella pneumoniae targets an EGF receptor-dependent pathway to Giessen, Germany subvert inflammation. (in preparation). Partners: Lothar Jänsch, Uwe Kärst, Helmholtz Centre for Infection Research,  Martinez-Soria N, Maeurer A, Meyer TF, García-del Portillo F. Salmonella exploits the Akt, Braunschweig, Germany ERK1/2, CK1 and CDK5 to reduce growth within fibroblasts (in preparation). Jürgen Kreft, Michael Kuhn, Dagmar Beier, University of Würzburg, Germany  Christner M, Franke GC, Schommer N, Wendt U, Wegert K, Pehle P, Kroll G, Schulze C, Pascale Cossart, Hélène Bierne, Institut Pasteur, Paris, France; Francisco García-del Portillo, Buck F, Mack D, Aepfelbacher M, Rohde H. (2009). The giant extracellular matrix binding Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain protein of Staphylococcus epidermidis mediates biofilm accumulation and attachment Mariela Scortti, University of León, Spain; Didier Cabanes, Institute for Molecular and Cell to fibronectin. Mol. Microbiol. 75: 187 – 207. Biology (IBMC), Porto, Portugal  Schommer NN, Christner M, Hentschke M, Ruckdeschel K, Aepfelbacher M, Rohde H. Yair Aharonowitz, Roded Sharan Tel Aviv University, Ramat Aviv, Israel (2011) Staphylococcus epidermidis uses distinct mechanisms of biofilm formation to Abstract: The proposal SPATELIS examined bacterial and cellular pathways induced interfere with phagocytosis and activation of mouse macrophage-like cells 774A.1. following L. monocytogenes infection. Highlights of these studies include: Discovery of ActA Infection and Immunity. 79(6):2267-76. as a major effector for escape of L. monocytogenes from autophagy. Identification of new  Köberle M, Klein-Günther A, Schütz M, Fritz M, Berchtold S, Tolosa E, Autenrieth IB, Bohn virulence factors by in vivo transcriptional profiling of L. monocytogenes including LapB, E. (2009) Yersinia enterocolitica targets cells of the innate and adaptive immune system a LPXTG surface adhesin. Detection of a secreted virulence factor of L. monocytogenes by injection of Yops in a mouse infection model. PLoS Path. 5(8):e1000551. targeting the host nucleus during infection. Characterization of the human protein BAHD1,  Kern JM, Maass V, Maass M. (2009) Molecular pathogenesis of chronic Chlamydia a novel protein involved in chromatin compaction and gene silencing, as a target of L. pneumoniae infection: a brief overview. Clin Microbiol Infect. 15:36-41. monocytogenes infection. Discovery of the cell-cycle kinase Nek9 as a novel target for  Kern JM, Maass V, Maass M. (2009) Chlamydia pneumoniae-induced pathological InlB-mediated signalling and description of the cellular phosphokinome induced by InlB. signaling in the vasculature.FEMS Immunol Med Microbiol. 55:131-9. Identification of cell wall proteins associated with peptidoglycan in L. monocytogenes as  virus replication. Nature 463, 818-822. well as the secretome and surface proteome of L. ivanovii strain PAM55. Characterization Patents related to the funded project of the 2-component system controlling cell envelope stress response of L. monocytogenes.  MPIIB: International patent application PCT/EP2011/053716, Pharmaceutical The gene architecture, expression and regulation of the anaerobic ribonucleotide reductase composition for the treatment of chlamydial infection (RNR) system, an essential enzyme for anaerobic growth. Development of Galleria mellonella as an invertebrate model for the study of Listeria virulence. Bioinformatic tools integrating systematic ecological data to predict strong competition between L. monocytogenes and Lactococcus lactis within the gut. Publications related to the funded project:  Freilich S, Kreimer A, Borenstein E, Gophna U, Sharan R, Ruppin E. Decoupling Environment-Dependent and Independent Genetic Robustness across Bacterial Species. PLoS Comput Biol 6:e1000690, 2010.  Freilich S, Kreimer A, Meilijson, Gophna U, Sharan R, Ruppin E. The large-scale organization of the bacterial network of ecological co-occurrence interactions. Nucleic Acids Res 38:3857-68, 2010.  Guillet C, Join-Lambert O, Le Monnier A, Leclerc A, Mechai F, Amzer-Buneel M, Bielecka M, Scortti M, Disson O, Berche P, Vazquez-Boland JA, Lortholary O, Lecuit M. 2009. Human listeriosis caused by Listeria ivanovii. Emerg Infect Dis 16:136-8, 2010.  Kuenne C, Voget S, Pischimarov J, Oehm S, Goesmann A, Daniel R, Hain T, Chakraborty T. Comparative analysis of plasmids in the genus Listeria. PLoS One 5, 2010.  Mohamed W, Sethi S, Darji A, Mraheil MA, Hain T, Chakraborty T. Antibody targeting the ferritin-like protein controls Listeria infection. Infect Immun 78:3306-14, 2010.  Personnic N, Bruck S, Nahori MA, Toledo-Arana A, Nikitas G, Lecuit M, Dussurget O, Cossart P, Bierne H. The stress-induced virulence protein InlH controls interleukin-6 |50 51 |

production during murine listeriosis. Infect Immun 78:1979-89, 2010. ActA-mediated escape from autophagic recognition. Nat Cell Biol 11:1233-40, 2009.  Reis O, Sousa S, Camejo A, Villiers V, Gouin E, Cossart P, Cabanes D. LapB, a novel Listeria  Barbuddhe SB, Maier T, Schwarz G, Kostrzewa M, Hof H, Domann E, Chakraborty T, Hain monocytogenes LPXTG surface adhesin required for entry into eukaryotic cells and T. Rapid identification and typing of Listeria species by matrix-assisted laser desorption virulence. J Infect Dis 202:551-62, 2010. ionization-time of flight mass spectrometry. Appl Environ Microbiol 74:5402-7, 2008.  Steinweg C, Kuenne CT, Billion A, Mraheil MA, Domann E, Ghai R, Barbuddhe SB, Kärst U,  Demuth A, Aharonowitz Y, Bachmann TT, Blum-Oehler G, Buchrieser C, Covacci A, Dobrindt Goesmann A, Pühler A, Weisshaar B, Wehland J, Lampidis R, Kreft J, Goebel W, Chakraborty U, Emödy L, van der Ende A, Ewbank J, Fernández LA, Frosch M, Portillo FG-d, Gilmore MS, T, Hain T. Complete genome sequence of Listeria seeligeri, a nonpathogenic member of Glaser P, Goebel W, Hasnain SE, Heesemann J, Islam K, Korhonen T, Maiden M, Meyer TF, the genus Listeria. J Bacteriol 192:1473-4, 2010. Montecucco C, Oswald E, Parkhill J, Pucciarelli MG, Ron E, Svanborg C, Uhlin BE, Wai SN,  Bekel T, Henckel K, Küster H, Meyer F, Mittard Runte V, Neuweger H, Paarmann D, Rupp O, Wehland J, Hacker J. Pathogenomics: An updated European Research Agenda. Infection, Zakrzewski M, Pühler A, Stoye J, Goesmann A: The Sequence Analysis and Management Genetics and Evolution 8:386-393, 2008. System – SAMS-2.0: Data management and sequence analysis adapted to changing  Hain T, Hossain H, Chatterjee SS, Machata S, Volk U, Wagner S, Brors B, Haas S, Kuenne requirements from traditional to ultrafast sequencing technologies. CT, Billion A, Otten S, Pane-Farre J, Engelmann S, Chakraborty T. Temporal transcriptomic J Biotechnol 140:3-12, 2009. analysis of the Listeria monocytogenes EGD-e sigmaB regulon. BMC Microbiol  Bierne H, Tham TN, Batsche E, Dumay A, Leguillou M, Kernéis-Golsteyn S, Regnault B, 28:8-20, 2008. Seeler JS, Muchardt C, Feunteun J, Cossart P. Human BAHD1 promotes heterochromatic  Hain T, Otten S, von Both U, Chatterjee SS, Technow U, Billion A, Ghai R, Mohamed W, gene silencing. Proc Natl Acad Sci U S A 106:13826-31, 2009. Domann E, Chakraborty T. A novel bacterial artificial chromosome vector pUvBBAC for  Bigot A, Raynaud C, Dubail I, Dupuis M, Hossain H, Hain T, Chakraborty T, Charbit A. functional genomics in Listeria spp. Appl Environ Microbiol 74:1892-901, 2008. lmo1273, a novel gene involved in Listeria monocytogenes virulence. Microbiology  Klein J, Leupold S, Münch R, Pommerenke C, Johl T, Kärst U, Jänsch L, Jahn D, Retter I. 155:891-902, 2009. ProdoNet: identification and visualization of prokaryotic gene regulatory and metabolic  Blom J, Albaum S, Doppmeier D, Pühler A, Vorhölter F-J, Zakrzewski M, Goesmann A. networks. Nucleic Acids Res 36:W460–W464, 2008. EDGAR: A software framework for the comparative analysis of prokaryotic genomes.  Machata S, Tchatalbachev S, Mohamed W, Jänsch L, Hain T, Chakraborty T. Lipoproteins of BMC Bioinformatics 10:154, 2009. Listeria monocytogenes are critical for virulence and TLR2-mediated immune activation.  Camejo A, Buchrieser C, Couvé E, Carvalho F, Reis O, Ferreira P, Sousa S, Cossart P, J Immunol 181:2028-35, 2008. Cabanes D. In vivo transcriptional profiling of Listeria monocytogenes and mutagenesis  Baumgärtner M, Kärst U, Gerstel B, Loessner M, Wehland J, Jänsch L. Inactivation of identify new virulence factors involved in infection. PloS Pathogens 5:e1000449, 2009. Lgt allows systematic characterization of lipoproteins from Listeria monocytogenes J.  Dondrup M, Hüser AT, Mertens D, Goesmann A. An evaluation framework for statistical Bacteriol 189:313-324, 2007. tests on microarray data. J Biotechnol 140:18-26, 2009.  Ghai R, Chakraborty T. Comparative Microbial Genome Visualization using GenomeViz. Hundertmark C, Fischer R, Reinl T, May S, Klawonn F, Jänsch L. MS-specific noise In: Methods in Molecular Biology: Comparative Genomics. Edited by Bergman N. Humana model reveals the potential of iTRAQTM in quantitative proteomics. Bioinformatics Press. ISBN13: 978-1-58829-693-1, ISBN10: 1-58829-693-8, 2007. 25:1004-11, 2009.  Hain T, Chatterjee SS, Ghai R, Kuenne CT, Billion A, Steinweg C, Domann E, Kärst U, Jänsch  Mukherjee K, Altincicek B, Hain T, Domann E, Vilcinskas A, Chakraborty T. Galleria L, Wehland J, Eisenreich W, Bacher A, Joseph B, Schär J, Kreft J, Klumpp J, Loessner MJ, mellonella as a model system for studying Listeria pathogenesis. Appl Environ Microbiol. Dorscht J, Neuhaus K, Fuchs TM, Scherer S, Doumith M, Jacquet C, Martin P, Cossart P, 76:310-7, 2010. 5. Ogawa M, Nakagawa I, Yoshikawa Y, Hain T, Chakraborty T, Sasakawa Rusniock C, Glaser P, Buchrieser C, Goebel W, Chakraborty T. Pathogenomics of Listeria C. Streptococcus-, Shigella-, and Listeria-induced autophagy. Methods Enzymol spp. Int J Med Microbiol 297:541-57, 2007. 452:363-81, 2009.  Scortti M, Monzó HJ, Lacharme-Lora L, Lewis DA, Vázquez-Boland JA. The PrfA virulence  Nestler U, Rollnik S, Schulz C, Chakraborty T, Domann E, Hain T. Expression of the reporter regulon. Microbes Infect 9:1196-207, 2007. genes lacZ and EGFP in human glioblastoma cells using Listeria monocytogenes as  van der Veen S, Hain T, Wouters JA, Hossain H, de Vos WM, Abee T, Chakraborty T, vector for gene transfer. Neurol Res 31:859-68, 2009. Wells-Bennik MH. The heat-shock response of Listeria monocytogenes comprises  Reinl T, Nimtz M, Hundertmark C, Johl T, Kéri G, Wehland J, Daub H, Jänsch L. Quantitative genes involved in heat shock, cell division, cell wall synthesis, and the SOS response. phosphokinome analysis of the Met pathway activated by the invasin InlB from Listeria Microbiology 153:3593-607, 2007. monocytogenes. Mol. Cell Proteomics 8:2778-95, 2009.  Yoshikawa Y, Ogawa M, Hain T, Chakraborty T, Sasakawa C. Listeria monocytogenes ActA is a key player in evading autophagic recognition. Autophagy 5:1220-1, 2009.  Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C. Listeria monocytogenes |52 53 |

Second Call for Proposals: Title Project Leader/ Project Partners Coordinator The second joint call of ERA-NET PathoGenoMics, entitled: “Applied pathogenomics: prevention, diagnosis, treatment and monitoring of infectious diseases in humans” was Functional genomics of host- issued in 2008. The requirements set out for project proposals stipulated that they focus pathogen interactions using Philippe Sansonetti, FR on the prevention, diagnosis, treatment and monitoring of diseases caused by bacterial high-throughput screenings: José Antonio Thomas F. Meyer, DE a novel approach towards Bengoechea, ES Thomas Rudel, DE and fungal pathogens. Applicants were also required to demonstrate ties with at least one identifying therapeutic/ Carmen Buchrieser, FR clinical and/or industrial partner. prophylactic targets

Members of the Scientific Advisory Board (SAB) of the second call: Jörg Hacker, DE Pathogenomic approach to Timo Korhonen, FI explore the use of bacterial Levente Emõdy, HU Name Institution/company HUlrich Dobrindt, interference as alternative Istvan Wittmann, HU DE treatment of recurrent urinary Eliora Ron, IL tract infections Catharina Svanborg/ Björn Wullt, SE Prof. Dr. Martin Maiden (chair) University of Oxford, Oxford, United Kingdom

Patrick Plésiat, FR Juan Luis Ramos, ES Isabel Sá-Correia, PT Dr. Fabrizzio Arigoni Nestlé Research Centre, Lausanne, Switzerland Sophie de ADHRES-Signature Project Soeren Molin, DK Bentzmann, FR Catherine Nguyen, FR Bio-Iliberius R&D, ES Gwennaele Fichant, FR Prof. Dr. Hillel Bercovier Hebrew University of Jerusalem, Jerusalem, Israel

sncRNAomics - High throughput comparative Maja Rupnik, SI sncRNAome analysis in Axel Hartke, FR University of Aberdeen, Aberdeen, United major Gram-positive human Prof. Dr. Neil Gow Torsten Hain, DE Bernd Kreikemeyer, DE Kingdom pathogenic bacteria: functional Susanne Engelmann, DE characterization by a systems Thomas Hartsch, DE biology approach and peptide nucleic acid drug design

Prof. Dr. Guido Grandi Novartis Vaccines, Siena, Italy

Hubertus Haas, AT Transcriptional networks Gerhard Braus, DE controlling virulence in Antonio Di Pietro, Sven Krappmann, DE filamentous fungal pathogens ES Federal Institute of Technology, Zurich, Ana Conesa, ES Prof. Dr. Wolf-Dietrich Hardt (TRANSPAT) Switzerland Roland Beffa, FR

The cell wall as a target to Jean-Paul Latgé, FR Projects funded: improve antifungal therapy Axel Brakhage, DE Emilia Mellado Terrado, ES against Aspergillosis Olga Geniallaud, ES Title Project Leader/ Project Partners Coordinator

Genome wide screening Bruno Dupuy, FR of the human pathogen Frederic Barbut, FR Seppo Meri, FI Pathogenomic of increased Neisseria meningitidis for Maja Rupnik, SI Adriano O. Henriques, PT Ulrich Vogel, DE Muhamed-Kheir Taha, FR Clostridium difficile virulence proteins enhancing serum Alexander Indra, AT Jan Poolman, GSKbio, BE resistance and evaluation of Wolfgang Liebl, DE their vaccine potential |54 55 |

Title Project Leader/ Project Partners All the following project abstracts were written by the project coordinators who are solely Coordinator responsible for their content

Transcriptome-based Kamil Önder, AT Monitoring and Eradication of Matthias Maass, Project name: Genome wide screening of the human pathogen Neisseria meningitidis for Mirja Puolakkainen, FI Chronic Chlamydial Infection - AT Dezso Peter Virok, HU proteins enhancing serum resistance and evaluation of their vaccine potential (Acronym: na) ChlamyTrans Coordinator: Ulrich Vogel, University of Würzburg, Germany Partners: Muhamed Taha, Institut Pasteur, Paris, France

Emmanuelle Charpentier, SE Seppo Meri, Hartmann Institute, Helsinki, Finland Mechanisms and modulation Ilkka Julkunen, FI GlaxoSmithKline biologicals, Belgium of innate immune responses to Pavel Kovarik, AT Sylvia Knapp, AT Streptococcus pneumoniae and Abstract: The aim of CoMeVac was to identify proteins of Neisseria meningitidis contributing Claire Poyart, FR S. pyogenes Estzter Nagy Intercell AG, AT to serum resistance. A semi-throughput screen for serum resistant meningococci revealed three mutant classes involving the adhesin Opc, LPS immunotype switch, and pilus gene conversion (Hubert et al., in revision). Johannes Hegemann, DE Global regulator mutants were analysed for altered deposition of complement factors. Hubertus Haas, Dmitrij Frishma, DE Austria Host-pathogen protein- Philippe Schmitt-Kopplin, DE The complete regulon of the Zinc uptake regulator Zur consecutively was established by protein interactomes and Romé Voulhoux, FR Thomas Rattei, DE microarray analysis. The meningococcal Zur box was characterized and binding of Zur to "The quality their influence on the host Agathe Subtil, FR of the science metabolome Matthias Horn, AT the Zur box was proven in vitro (Pawlik et al., submitted). also benefits Jan Rupp, DE Proteomic and transcriptomic comparison of three genetically related strains revealed Ana Conesa Cegarra, ES from the two proteins contributing to serum resistance of the invasive isolate. These proteins are common currently followed in more detail. funding, since Vitor A. P. Martins dos Santos, NL Analysis of manganese export in meningococci identified MntX as an important novel it increases Development, prevention and Manuel Ferrer, ES factor contributing both to serum resistance and survival in animals (Veyrier et al. PLoS early diagnostic detection of Andres Moya, ES the motivation Pathog. 2011). to solve Clostridium difficile - associated Stephan Ott, DE Laya Pedrola, ES pseudomembranous colitis - an Bernhard Ronacher, AT Construction of transgenic mice expressing a human complement regulator allowed common interdisciplinary network Miguel Godinho, PT studies of meningococcal complement resistance in vivo (Taha et al. unpublished) problems." Christoph Reschreiter, AT In summary, the project contributed to the understanding of serum resistance of meningococci. Promising proteins will now be investigated for their potential as novel Identification of hot spots vaccine candidates. The new mouse model will be of general value for future studies in Dorothea Orth, AT of divergence and rapidly Alexander Nicolas Barnich, FR the field. changing genes within Shiga Mellmann, DE Eduard Torrents, ES toxin-producing Escherichia coli Publications related to the funded project:  Veyrier FJ, Boneca IG, Cellier MF, Taha MK. A novel metal transporter mediating manganese export (MntX) regulates the Mn to Fe intracellular ratio and Neisseria meningitidis virulence. PLoS Pathog. 2011 Sep;7(9):e1002261.  Claus H, Jördens MS, Kriz P, Musilek M, Jarva H, Pawlik MC, Meri S, Vogel U. Capsule null locus meningococci: typing of antigens used in an investigational multicomponent meningococcus serogroup B vaccine. Vaccine. 2012;30(2):155-60. |56 57 |

Project name: Functional genomics of host-pathogen interactions using high-throughput Project name: Pathogenomic approach to explore the use of bacterial interference as screenings: a novel approach towards identifying therapeutic/prophylactic targets alternative treatment of recurrent urinary tract infection (Acronym: UTI Interference) (Acronym: FUNGEN) Coordinator: Ulrich Dobrindt, Institute of Hygiene, University of Münster, Germany Coordinator: José A. Bengoechea, Fundación investigacion Sanitaria Illes Balears, Spain Partners: Timo Korhonen, University of Helsinki, Department of Biological and Environmental Partners: Thomas F Meyer, Max Planck Institute for Infection Biology, Germany Sciences, General Microbiology, Finland Philippe J. Sansonetti, Institut Pasteur, France Levente Emődy, University Medical School – University of Pécs,Department of Medical Carmen Buchrieser, Institut Pasteur, France Microbiology and Immunology, Hungary & István Wittmann, University of Pécs, Department Thomas Rudel , University Wurzburg, Germany of Medicine and Nephrology, Hungary Abstract: The increasing number of bacteria resistant to all antibiotics and antimicrobials Eliora Z. Ron, Tel Aviv University,Department of Molecular Microbiology and make necessary to develop therapeutics based on new targets/approaches. Among others, Biotechnology, Israel one of the most promising approaches is to understand host-pathogen interactions at the Catharina Svanborg and Björn Wullt, Lund University, Section of Microbiology, Immunology cellular and molecular levels in order to identify cellular pathways important for infection and Glycobiology, Sweden as well as pathogen determinants involved in disease progression. The identified host Abstract: Since many uropathogens are versatile and highly resistant to antibiotics, obvious and pathogen targets may lead to development of innovative therapies based on the treatments, including standard vaccination procedures, are inefficient. In some individuals, modulation of the host-pathogen interface. Ulrich recurrent urinary tract infection (UTI) severely impacts quality of life. Antibiotic treatment is, FUNGEN aimed to identify novel pathogen determinants targeting crucial host functions. Dobrindt, in most cases, effective but when repeated courses or long-term prophylactics are needed, Our efforts were placed on the study of four important human pathogens: Legionella Germany the occurrence of side effects becomes problematic. These include bacterial selection for pneumophila, Helicobacter pylori, Neisseria gonorrhoeae and Klebsiella pneumoniae. Using "In microbial resistance, disturbance of the patient’s own normal microbial flora, gastrointestinal high-throughput functional genomics methods, FUNGEN has uncovered: hitherto unknown comparison, side effects and allergic reactions. There is a strong need for the development of alternatives in other EU pathways targeted by Neisseria for dissemination; a novel system used by Klebsiella to to antibiotic treatment, such as bacterial interference, i.e. bacterial interaction by the initiatives deliver a toxin inside human cells; and the strategies employed by Klebsiella, Legionella one has to competition of nutrients and by bacterial production of toxic molecules. Our consortium aims and Helicobacter to subvert the activation of inflammatory responses, chiefly the NF-B spend much at a deeper understanding of the molecular mechanisms of ABU E.coli adaptation in the pathway. Using translational drug clinical development models, FUNGEN partners are more time on urinary bladder and at the development of a therapeutic strategy based on ABU E.coli to treat currently investigating whether it is feasible to modulate the identified host targets in vivo paperwork, recurrent UTI. We perform functional genomic analyses of host adaption to identify important to clear bacterial infections in add-on with antibiotics. and bacterial traits required for long-term growth in the urinary tract, and to characterize the steps Publications related to the funded project: coordination, responsible for turning an uropathogenic bacterium into a non-pathogenic commensal. We  Rolando M, Buchrieser C. (2012) Post-translational modifications of host proteins leaving less also work on the safety of E.coli ABU strain 83972 used for deliberate colonization of patients by Legionella pneumophila: a sophisticated survival strategy. Future Microbiology. time for suffering from chronic or recurrent UTI. 7(3):369-81. scientific Publications related to the funded project:  Lomma M, Dervins-Ravault D, Rolando M, Nora T, Newton HJ, Sansom FM, Sahr T, research."  Lehti, T.A., Heikkinen, J., Korhonen, T.K., Westerlund-Wikström, B. (2012) The response Gomez-Valero L, Jules M, Hartland EL, Buchrieser C. (2010) The Legionella pneumophila regulator RcsB activates expression of Mat fimbriae in meningitic Escherichia coli. J F-box protein Lpp2082 (AnkB) modulates ubiquitination of the host protein parvin B and Bacteriol. Epub ahead of print PMID: 22522901. promotes intracellular replication. Cellular Microbiology 12(9):1272-1291.  Salvador, E., Wagenlehner, F., Köhler, C.D., Mellmann, A., Hacker, J., Svanborg, C., Dobrindt,  D Moranta, V Regueiro, C March, E Llobet, J Margareto, E Larrate, J Garmendia, JA U. (2011) Asymptomatic bacteriuria E. coli isolates from healthy individuals versus Bengoechea. 2010. Klebsiella pneumoniae capsule polysaccharide impedes the expression hospital patients: long-term bladder colonization selects for attenuated virulence of -defensins by airway epithelial cells. Infection and Immunity. 78:1135-1146. phenotypes. Infect Immun. 80(2):668-678.  V. Reguerio, D. Moranta, CG Frank, J Margareto, E. Larrate, J Garmendia, JA Bengoechea.  Grönberg-Hernández, J., Sundén, F., Connolly, J., Svanborg, C., Wullt, B. (2011) Genetic 2011 Klebsiella pneumoniae subverts the activation of inflammatory responses in a control of the variable innate immune response to asymptomatic bacteriuria. PLoS One. NOD1-dependent manner. Cellular Microbiology. 13:135-153 6(11):e28289.  C. March, D. Moranta, V. Regueiro, E. Llobet, A. Tomás, J. Garmendia J, JA Bengoechea. Oren, Y., Biran, D., Dobrindt, U., Ron, E.Z. Urine-induced transcriptomic changes in UTI 2011 Klebsiella pneumoniae outer membrane protein A is required to prevent the bacteria and their non-pathogenic derivatives. In preparation. activation of airway epithelial cells. Journal Biological Chemistry. 286:9956-9967  Köves, B., Salvador, E., Grönberg-Hernandez, J., Zdziarski, J., Wullt, B., Dobrindt, U., Svanborg, C. Symptomatic UTI episodes caused by E. coli 83972. In preparation. |58 59 |

Project name: ADHRES-Signature Project  Daddaoua, A., S. Fillet, M. Fernández, Z. Udaondo, T. Krell and J.L. Ramos.(2012) Carbon Coordinator: Sophie de Bentzmann, UMR CNRS , AMU, Marseille, France catabolism genes and the virulence toxA gene in Pseudomonas aeruginosa. PLoS One, Partners: Patrick Plésiat, Laboratoire de Bactériologie- Faculté de Médecine- in revision. Besancon, France  Duque E, de la Torre J, Bernal P, Molina-Henares MA, Alaminos M, Espinosa-Urgel M, Juan Luis Ramos, CSIC, SPAIN Roca M, Fernández M, de Bentzmann S, and Ramos JL. (2012) Identification of reciprocal Isabel Sá-Correia, IBB-Institute for Biotechnology and Bioengineering/CEBQ, Instituto adhesion genes in pathogenic and non-pathogenic Pseudomonas. Env Microbiol, 28 Superior Técnico, Portugal MAR 2012 | DOI: 10.1111/j.1462-2920.2012.02732. Soeren Molin, Technical University of Denmark, Denmark  Fernández, M., S. Conde, J. de la Torre, C. Molina-Santiago, J.L. Ramos, and E. Duque. Cathy Nguyen, U1090, TAGC, Marseille, France (2012) Mechanisms of resistance to chloramphenicol by Pseudomonas putida KT2440. BIO-ILIBERIS R&D, Grenada, Spain Antimicrob Agent Chem, 56:1001-9. Gwennaele Fichant, UMR 5100, Toulouse III University, France  Coutinho C.P., de Carvalho C.C.C.R., Madeira A., Pinto-de-Oliveira A., Sá-Correia I. (2011) Abstract: Bacterial sedentary lifestyle is an aggravating factor in infections and Burkholderia cenocepacia phenotypic clonal variation during a 3.5-year colonization in represents a major therapeutical problem. It limits penetration of antibiotics, favors the lungs of a cystic fibrosis patient. Infect Immun, 79:2950-2960. horizontal acquisition of new resistance genes and activates specific resistance  de Bentmann S, and Plésiat P. (2011). Pseudomonas aeruginosa : une virulence complexe. mechanisms, thus promoting emergence of multi-resistant strains. The aim of the Revue Francophone des laboratories, 435: 73-81. ADHRES-Signature project was to elucidate how a particular molecular composition of  Giraud C, Bernard CS, Calderon V, Yang L, Filloux A, Molin S, Fichant G, Bordi C, and de the biofilm matrix (ADH) could condition antibiotic resistance (RES) in pseudomonads- Bentzmann S. (2011) The PprA-PprB two-component system activates CupE, the first related species (Pseudomonas aeruginosa, Pseudomonas putida and Burkholderia non-archetypal Pseudomonas aeruginosa chaperone-usher pathway system assembling cepacia complex (Bcc)). Several ADHRES signatures were dissected in vitro, highlighting fimbriae. Environ Microbiol, 13:666-683. that molecular composition of the biofilm matrix and antimicrobial resistance can widely  de Bentzmann S, and Plésiat P. (2011) The Pseudomonas aeruginosa opportunistic vary according to environmental pressure. Using systematic transposon mutagenesis pathogen and human infections. Environ Microbiol, 13:1655-1665. in different clones isolated from patients and their high throughput phenotypic screen  Giraud C, de Bentzmann S. (2011) Inside the complex regulation of Pseudomonas for resistance and adhesion, this project has unraveled and characterized new ADH and aeruginosa chaperone usher systems. Environ Microbiol . Dec 22. doi: 10.1111/j.1462- RES genes that were further confirmed to play a role in acute or chronic infections using 2920.2011.02673.x. transcriptomic and proteomic analyses from freshly isolated clones, further confirming  Bordi C, de Bentzmann S (2011) Hacking into bacterial biofilms: a new therapeutic particular ADHRES signatures in human infections. Thus ADHRES signature represents challenge. Annals of Intensive Care, 1:19 surely a good diagnostic or prognostic tool, but also a good basis for development of  Muller C., P. Plésiat, and K. Jeannot. A two-component regulatory system interconnects new antimicrobial molecules and for adapted anti-infectious strategies. The project has resistance to polymyxins, aminoglycosides, fluoroquinolones, and ß-lactams in generated 3 libraries, multigenomic microarrays and 13 new genomes were sequenced. Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy. 2011, 55: 1211-1221. Publications related to the funded project:  Yang, L., Rau, M.H., Yang, L., Hoiby, N., Molin, S., and Jelsbak, L. (2011) Bacterial adaptation  Calderon V, Barriot R, de Bentzmann S, Quentin Y and Fichant G. Phylogenetic analyses during chronic infection revealed by independent component analysis of transcriptome of the CU systems. In preparation. data. BMC Microbiol, 18: 184-189. Calderon V, Barriot R, de Bentzmann S, Quentin Y and Fichant G. Dynamic Evolution of CU  Giraud C, Bernard C, Ruer S, de Bentzmann S. (2010) Biological “glue” and “Velcro”: pathways in Escherichia coli strains. In preparation. Molecular tools for adhesion and biofilm formation in the hairy and gluey bug  Molina L, Duque E, Fernández M, Udaondo Z, Roca A, Porcel M, de la Torre J, Segura A, Pseudomonas aeruginosa». Env Microbiol Rep, 2: 343–358. Plesiat P, Jeannot K, Ramos JL. (2012) Antibiotic resistance markers in the genome of Pseudomonas putida PC9 isolated from a CF patient. Antimicrobial Agents and Chemotherapy. Submitted.  Bigot S, Faure L, Llamas M, de Bentzmann S. (2012) Phosphate starvation controls TPS genes in Pseudomonas aeruginosa through PhoB-PhoR and VreI ECF sigma factor. J Bact, Submitted.  de Bentzmann S,. Bernard CS, Giraud C, Calderon V, Ewald F, Plésiat P, Nguyen C, Grunwald D, Attrée I, Fauvarque MO, Jeannot K, and Bordi C. (2012) Hyper-biofilm, hypo-virulent and antimicrobial sensitive phenotypes in Pseudomonas aeruginosa through the control of the two-component system PprAB . Plos Pathogens, in revision. |60 61 |

Project name:sncRNAomics - High throughput comparative sncRNAome analysis in major macrophages**.Mraheil MA, Billion A, Mohamed W, Mukherjee K, Kuenne C, Pischimarov Gram-positive human pathogenic bacteria: functional characterisation by a systems J, Krawitz C, Retey J, Hartsch T, Chakraborty T, Hain T. Nucleic Acids Res. 2011.39(10):4235- biology approach and peptide nucleic acid drug design (Acronym: sncRNAomics) 48. Coordinator: Torsten Hain, Justus-Liebig-University Giessen, Institute of Medical  Comparative genome-wide analysis of small RNAs of major Gram-positive pathogens: Microbiology, Giessen, Germany from identification to application**. Partners: Maja Rupnik, University of Maribor, Faculty of Medicine, Department for Mraheil MA, Billion A, Kuenne C, Pischimarov J, Kreikemeyer B, Engelmann S, Hartke A, Microbiology Maribor, Slovenia Giard JC, Rupnik M, Vorwerk S, Beier M, Retey J, Hartsch T, Jacob A, Cemič F, Hemberger J, Axel Hartke, Université de Caen, Laboratoire de Microbiologie de l’Environnement Esplanade Chakraborty T, Hain T. Microb Biotechnol. 2010. 3(6):658-76. de la Paix, Caen Cedex, France  Comparative analysis of plasmids in the genus Listeria. Bernd Kreikemeyer, University of Rostock, Institute of Medical Microbiology, Virology and Kuenne C, Voget S, Pischimarov J, Oehm S, Goesmann A, Daniel R, Hain T, Chakraborty T. Hygiene, Rostock, Germany PLoS One. 2010. 2;5(9). pii: e12511. Susanne Engelmann, Ernst-Moritz-Arndt-University, Institute of Microbiology Greifswald,  Identification and Role of Regulatory Non-Coding RNAs in Listeria monocytogenes. Germany Thomas Hartsch, Genedata Bioinformatik GmbH, Planegg-Martinsried, Germany Izar B, Mraheil MA, Hain T. Int J Mol Sci. 2011;12(8):5070-9. Abstract: Novel anti-infectives are of high priority for global health care. Small non-coding  Universal stress proteins are important for oxidative and acid stress resistance and growth RNAs (sncrRNAs) are an emerging class of gene expression regulators and could provide of Listeria monocytogenes EGD-e in vitro and in vivo. potential anti-infective targets. Seifart Gomes C, Izar B, Pazan F, Mohamed W, Mraheil MA, Mukherjee K, Billion A, In the ERA-NET PathoGenoMics-2 sncRNAomics project, we identified and characterized Aharonowitz Y, Chakraborty T, Hain T. PLoS One. 2011;6(9):e24965. several new small non-coding RNAs (sncRNAs) in five investigated Gram-positive human  Genome-wide identification of small RNAs in the opportunistic pathogen Enterococcus pathogenic bacteria. Additionally, we have reported the discovery of 150 putative sncRNAs faecalis V583**. in Listeria monocytogenes under extracellular and intracellular growth conditions (Mraheil Shioya K, Michaux C, Kuenne C, Hain T, Verneuil N, Budin-Verneuil A, Hartsch T, Hartke A, et al., 2011). The application of intergenic tiling microarrays allowed the identification of 75 Giard JC. PLoS One. 2011. 6(9):e23948. additional putative sncRNAs candidates under different stress conditions in Enterococcus  Non-coding RNA detection methods combined to improve usability, reproducibility faecalis (Shioya et al., 2011). and precision. In Clostridium difficile 46 sncRNAs candidates were detected genomewide. Global sncRNA Raasch P, Schmitz U, Patenge N, Vera J, Kreikemeyer B, Wolkenhauer O. BMC analysis for Streptococcus pyogenes revealed 55 potential candidates, whereas 268 Bioinformatics. 2010. 29;11(1):491 sncRNAs candidates were detected in Staphylococcus aureus.  Genomic and proteomic characterization of Staphylococcus aureus mastitis isolates of In collaboration with the German Cancer Research Center (DKFZ), antisense PNAs (peptide bovine origin. nucleic acids), were successfully applied to inhibit growth of Listeria monocytogenes, Carmen Wolf, Harald Kusch, Stefan Monecke, Dirk Albrecht, Silva Holtfreter, Christof Streptococcus pyogenes and Clostridium difficile. von Eiff, Wolfram Petzl, Pascal Rainard, Barbara M. Bröker, and Susanne Engelmann. Moreover, the development of a diagnostic system based on PNA binding to sncRNAs Proteomics. 2011, 11(12):2491-502. at the University of Applied Sciences (THM), Giessen, was furthered by choosing PNAs  Identification of novel growth phase and media-dependent small non-coding RNAs in specifically labelled with hydrophobic, fluorescent molecules, which bind very tightly to Streptococcus pyogenes M49 nitrocellulose membranes. PNAs bound to superparamagnetic nanoparticles were used to using intergenic tiling arrays**. create a lateral flow assay test system. Proof of principle was achieved by using Listeria- Nadja Patenge, André Billion, Peter Raasch, Jana Normann, Aleksandra Wisniewska- specific PNAs with complimentary DNA sequences. Kucper, Julia Retey, Valesca Boisguérin, Thomas Hartsch, Torsten Hain, Bernd Kreikemeyer. Publications related to the funded project: In resubmission, BMC Genomics.  Comparative genomics and transcriptomics of lineages I, II, and III strains of Listeria  Parallel purification of Peptide Nucleic Acids for COMBO-FISH. monocytogenes. Hain T, Ghai R, Billion A, Kuenne CT, Steinweg C, Izar B, Mohamed W, Dauber, M.; Müller, P.; Hausmann, M.; Schnölzer, M.; Hoheisel, J and Jacob, A. In Mraheil M, Domann E, Schaffrath S, Kärst U, Goesmann A, Oehm S, Pühler A, Merkl R, resubmission, Nucleic Acid Res., 2011. Vorwerk S, Glaser P, Garrido P, Rusniok C, Buchrieser C, Goebel W, Chakraborty T. BMC  sRNAdb: small non-coding RNA database for gram-positive bacteria**. Genomics. 2012 Apr 24;13(1):144. Pischimarov J, Kuenne C, Billion A, Hemberger J, Cemič F, Chakraborty T, Hain T. In  microRNA response to Listeria monocytogenes infection in epithelial cells.Benjamin Izar, resubmission, BMC Genomics. Gopala Mannala, Mobarak A. Mraheil, Trinad Chakraborty, Torsten Hain. Int J Mol Sci.  New methods for rapid, sensitive quantification of nucleic acids based on Lateral flow 2012, (13) 1173-1185 assay formats**.  The intracellular sRNA transcriptome of Listeria monocytogenes during growth in Wagner S, Mengel P, Schäfer T, Hain, T, Jacob A, Cemic F & Hemberger J. to be submitted |62 63 |

to Biosensors & Bioelectronics Project name: Transcriptional networks controlling virulence in filamentous fungal pathogens ** joint publication (TRANSPAT) (Acronym: TRANSPAT) Patents related to the funded project: Coordinator: Antonio Di Pietro, University of Cordoba, Spain 2 Patent applications Partners: Hubertus Haas, Innsbruck Medical University, Austria  DE 10/2010 009161.8. (2010) Gerhard Braus, University of Göttingen, Germany Procedure to enhance the detection limit of magnetically labelled samples. Sven Krappmann, Research Center for Infectious Diseases Würzburg, Germany Inventors: Hemberger, J.; Cemic, F. Ana Conesa, Centro de Investigación Principe Felipe Valencia, Spain Patentee: University of Applied Sciences, Giessen-Friedberg Roland Beffa, Bayer CropScience Lyon, France. EP 10 187 366.9. (2010) Abstract: Dissemination through the bloodstream represents a critical step in systemic  A new dimedon derivative and a method for purification of PNA and peptide oligomers. fungal infection. How filamentous fungi are able to survive in the hostile environment Inventors: Jacob, A.; Dauber, M.; Hoheisel, J.; Wiessler, M.; Fleischhacker, H.; Lorenz, P.; of human blood is largely unknown. The TRANSPAT project integrates genetic and Kliem, C. transcriptomic approaches to generate a high-resolution map of the fungal transcriptome Patentee: DKFZ, Heidelberg during growth in human blood. The aim is to define transcriptional networks of clinical 5 Patent applications filed relevance in Aspergillus and Fusarium, two important human pathogens. Using two  “Entdeckung von small non-coding RNAs (sncRNAs) des human pathogenen Bakteriums complementary approaches, custom oligoarrays and massively parallel sequencing of Listeria monocytogenes zur Anwendung als neue Targets für antibakterielle Stoffe” cDNA (RNA-seq), genome wide expression profiles were generated during early stages of Torsten Hain, Mobarak Abu Mraheil, Trinad Chakraborty, André Billion, Alexandra Amend- blood growth, leading to the identification of hundreds of genes whose transcript levels Förster, Universitiy of Giessen are significantly upregulated in Aspergillus and Fusarium during growth on human blood.  “Identifizierug von small non-coding RNAs (sncRNAs) des human pathogenen Bakteriums Fungal mutants in the key virulence transcription factors were also included in the analysis, Streptococcus pyogenes zur Anwendung als neue Targets für antibakterielle Stoffe” such as the developmental regulator Velvet, the regulator of secondary metabolism LaeA, Bernd Kreikemeyer, Nadja Patenge, Torsten Hain, Aleksandra Wisniewska-Kucper, André the iron-response factor HapX, the nitrogen regulator MeaB, the pH response factor PacC, Billion, Universitiy of Rostock and the homeodomain transcription factor Ste12. The results of this comprehensive  “Anwendung von antisense PNA gegen baketerielle sRNA als neuer Therapieansatz” transcriptome analysis provide new insights into the genetic programmes that determine Torsten Hain, Mobarak Abu Mraheil, Anette Jakob, Jörg Hoheisel dissemination of filamentous fungal pathogens in the human host, facilitating the Universitiy of Giessen, DKFZ, in preparation identification of novel antifungal targets.  “Methods for high affinity binding of polar molecules to membrane devices» Publications related to the funded project: Universitiy of Applied Sciences, Giessen  Prados-Rosales RC, Roldan-Rodriguez R, Serena C, Lopez-Berges MS, Guarro J, Martinez-  “Correlation-based enhancement of detection sensitivity for superparamagnetic particle del-Pozo A, Di Pietro A (2012) A PR-1 like protein of Fusarium oxysporum functions in based Lateral flow assay formats” virulence on mammalian hosts. J Biol Chem [Epub ahead of print.] Universitiy of Applied Sciences, Giessen  Navarro-Velasco GY, Prados-Rosales RC, Ortíz-Urquiza A, Quesada-Moraga E, Di Pietro Spin-off of the DKFZ/sncRNAomics A (2011) Galleria mellonella as model host for the trans-kingdom pathogen Fusarium Peps4LS GmbH oxysporum. Fungal Genet Biol 48:1124-1129. Dr. Anette Jacob, INF 583, 69120 Heidelberg  Pérez-Nadales E, Di Pietro A (2011) The membrane mucin Msb2 regulates invasive www.Peps4LS.de growth and plant infection in Fusarium oxysporum. Plant Cell 23:1171-1185. Products and services/research areas:  Rispail N, Di Pietro A (2010) The homeodomain transcription factor Ste12: Connecting Small scale peptide and synthesis and parallel purification fungal MAPK signalling to plant pathogenicity. Commun Integr Biol 3: 327-32. for the production of libraries and arrays  López-Berges MS, Rispail N, Prados-Rosales RC, Di Pietro A (2010) A nitrogen response Development of purification methods, drugs and diagnostic tools pathway regulates virulence functions in Fusarium oxysporum via the protein kinase TOR and the bZIP protein MeaB. Plant Cell 22: 2459-75.  Haas H (2012) Iron - A key nexus in the viriulence of Aspergillus fumigatus. Frontiers Microbiol 3:28  Yasmin S, Alcazar-Fuoli L, Gründlinger M, Puempel T, Cairns T, Blatzer M, Lopez JF, Grimalt JO, Bignell E, Haas H. (2011) Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A 109:497-504. |64 65 |

Schrettl M, Haas H. (2011) Iron homeostasis--Achilles› heel of Aspergillus fumigatus? Project name: The cell wall as a target to improve antifungal therapy against Invasive Curr Opin Microbiol 14:400-405. Aspergillosis (Acronym: AntiFun)  Schrettl M, Beckmann N, Varga J, Heinekamp T, Jacobsen ID, Jöchl C, Moussa TA, Wang Coordinator: Axel A. Brakhage, Leibniz Institute for Natural Product Research and Infection S, Gsaller F, Blatzer M, Werner ER, Niermann WC, Brakhage AA, Haas H. (2010) HapX- Biology – Hans Knoell Institute (HKI), Jena, Germany mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. Partners: Jean-Paul Latgé,Institut Pasteur, France PLoS Pathog 6:e1001124. Emilia Mellado, Servicio de Micología, Centro National de Microbiologia, Instituto de Salud  von Zeska Kress MR, Harting R, Bayram Ö, Christmann M, Irmer H, Valerius O, Schinke Carlos III, Spain J, Goldman GH, Braus GH (2012) The COP9 signalosome counteracts the accumulation Olga Geniallaud,Fundación Centro de Excelencia Medina, Spain of cullin SCF ubiquitin E3 RING ligases during fungal development. Mol Microbiol Abstract: Aspergillus fumigatus is the most important airborne human-pathogenic fungus. 83:1162-77. A. fumigatus can cause invasive aspergillosis (IA) in immunocompromised patients. In  Bayram O, Braus GH (2012) Coordination of secondary metabolism and development in the last two decades, the incidence of IA has increased three fold. Because therapeutic fungi: the velvet family of regulatory proteins. FEMS Microbiol Rev 36:1-24. intervention is limited, IA is associated with a high mortality rate above 30 %.  Sarikaya Bayram O, Bayram O, Valerius O, Park HS, Irniger S, Gerke J, Ni M, Han KH, Yu JH, The cell wall of A. fumigatus is a unique structure, which does not exist for human cells. It Braus GH (2010) LaeA control of velvet family regulatory proteins for light-dependent enables the fungus to resist against external aggressions, but, at the same time, it is its Achilles’ development and fungal cell-type specificity. PLoS Genet 6:e1001226. heel since it is a major drug target as shown by the commercial launch of echinocandins  Nahlik K, Dumkow M, Bayram O, Helmstaedt K, Busch S, Valerius O, Gerke J, Hoppert M, that block cell wall biosynthesis. By using methods of functional genomics coupled with Schwier E, Opitz L, Westermann M, Grond S, Feussner K, Goebel C, Kaever A, Meinicke sophisticated biochemical and genetic analysis, we obtained a comprehensive insight into P, Feussner I, Braus GH (2010) The COP9 signalosome mediates transcriptional and the biosynthesis of the cell wall and its regulation also under echinocandin stress. metabolic response to hormones, oxidative stress protection and cell wall rearrangement The results obtained in this research project will have a profound impact on knowledge during fungal development. Mol Microbiol 78:964-79. and technology exploitation. (i) The scientific basis for developing new treatment strategies  Braus GH, Irniger S, Bayram O (2010) Fungal development and the COP9 signalosome. for invasive aspergillosis was set. (ii) Drug-screening programmes were improved by Curr Opin Microbiol 13:672-6. developing a high-throughput methodology. (iii) New drug combinations potentially  Hartmann T, Cairns TC, Olbermann P, Morschhäuser J, Bignell EM, Krappmann S (2011) abolishing compensatory mechanisms were identified. (iv) Alternative screening methods Oligopeptide transport and regulation of extracellular proteolysis are required for avoiding classical animal models were evaluated. growth of Aspergillus fumigatus on complex substrates but not for virulence. Mol Publications related to the funded project: Microbiol 82:917-35.  Valiante V., Jain R., Heinekamp T., Brakhage A.A. 2009. The MpkA MAP kinase module  Hartmann T, Sasse C, Schedler A, Hasenberg M, Gunzer M, Krappmann S (2011) Shaping regulates cell wall integrity signaling and pyomelanin formation in Aspergillus fumigatus. the fungal adaptome--stress responses of Aspergillus fumigatus. Int J Med Microbiol Fungal Genet. Biol. 46: 909-918. 301:408-16.  Mouyna I., Kniemeyer O., Jank T., Loussert C., Mellado E., Aimanianda V., Beauvais A.,  Hartmann T, Dümig M, Jaber BM, Szewczyk E, Olbermann P, Morschhäuser J, Krappmann Wartenberg D., Sarfati J., Bayry J., Prévost M.C., Brakhage A.A., Strahl S., Huerre M., Latgé S (2010) Validation of a self-excising marker in the human pathogen Aspergillus J.P. 2010. Members of protein O-mannosyltransferase family in Aspergillus fumigatus fumigatus by employing the beta-rec/six site-specific recombination system. Appl differentially affect growth, morphogenesis and viability. Molecular Microbiology Environ Microbiol 76:6313-7. 76: 1205-1221.  Nueda MJ, Ferrer A, Conesa A (2011) ARSyN: a method for the identification and removal  Jain R., Valiante V., Remme N., Docimo T., Heinekamp T., Hertweck C., Gershenzon J., Haas of systematic noise in multifactorial time course microarray experiments. Biostatistics H., Brakhage A.A. 2011. The MAP Kinase MpkA controls cell wall integrity, oxidative stress [Epub ahead of print] response and iron adaptation in A. fumigatus. Molecular Microbiology 82: 39-53.  Tarazona S, García-Alcalde F, Dopazo J, Ferrer A, Conesa A (2011) Differential expression  Alcazar-Fuoli L., Clavaud C., Lamarre C., Aimanianda V., Seidl-Seiboth V., Mellado E., Latgé in RNA-seq: a matter of depth. Genome Res 21:2213-23. J.P. 2011. Functional analysis of the fungal/plant class chitinase family in Aspergillus  García-Alcalde F, García-López F, Dopazo J, Conesa A (2011) Paintomics: a web based fumigatus. Fungal Genet. Biol. 48: 418-429. tool for the joint visualization of transcriptomics and metabolomics data. Bioinformatics  Wong Sak Hoi J., Lamarre C., Beau R., Meneau I., Berepiki A., Barre A., Mellado E., Read N.D., 27:137-9. Latgé J.P., 2011. A novel family of dehydrin-like proteins is involved in stress response  Nueda MJ, Carbonell J, Medina I, Dopazo J, Conesa A. (2010) Serial Expression Analysis: a in the human fungal pathogen Aspergillus fumigatus. Molecular Biology of the Cell 22: web tool for the analysis of serial gene expression data. Nucleic Acids Res 38(Web Server 1896-1906. issue):W239-45.  Keller S., Macheleidt J., Jacobsen I., Heinekamp T., Brakhage A.A. 2011. Pyomelanin formation in Aspergillus fumigatus requires HmgX and the transcriptional activator |66 67 |

HmgR but is dispensable for virulence. PLoS One 6: e26604 Project name: Pathogenomics of increased Clostridium difficile virulence Acronym:  Mellado E., Alcazar-Fuoli L., Cuenca-Estrella M., Rodriguez-Tudela J.L. 2011. Role of CDIFFGEN Aspergillus lentulus 14-sterol demethylase (Cyp51A) in azole drug susceptibility. Coordinator: Maja Rupnik, Institute of Public Health Maribor, Maribor, Slovenia Antimicrob. Agents Chemother. 55: 5459-5468. Partners: Bruno Dupuy, Institut Pasteur, Paris, France  Alcazar-Fuoli L., Cuesta I., Rodriguez-Tudela J.L., Cuenca-Estrella M., Sanglard D., Mellado Frederic Barbut, Faculté de Médecine Pierre et Marie Curie, Paris, France E., 2011. Three-dimensional models of 14-sterol demethylase (Cyp51A) from Aspergillus Adriano O. Henriques, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction. Alexander Indra, Austrian Agency for Health and Food Safety, Vienna, Austria Int. J. Antimicrob. Agents 38: 426-434. Wolfgang Liebl, Technische Universität München, Freising, Germany  Alcazar-Fuoli L., Mellado E., Cuenca-Estrella M., Sanglard D., 2011. Probing the role of Abstract: Clostridium difficile is associated with infections in hospitals and in the point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast community and genotypes causing disease with higher mortality, severity and Saccharomyces cerevisiae. Med. Mycol. 49: 276-284. increased relapse rates are emerging worldwide.  Mortensen K.L., Jensen R.H., Johansen H.K., Skov M., Pressler T., Howard S.J., The aims of this project were to define C. difficile groups with increased virulence Leatherbarrow H., Mellado E., Arendrup M.C. 2011. Aspergillus species and other molds potential (‘hypervirulent strains’) and to analyze their genomic heterogeneity, as well in respiratory samples from patients with cystic fibrosis: a laboratory-based study with as the presence of known and/or new virulence factors, and their regulation. The focus on Aspergillus fumigatus azole resistance. J. Clin. Microbiol. 49: 2243-2251. Maja Rupnik, main strength of this project was therefore that it did not concentrated at a small  Alastruey-Izquierdo A., Cuesta I., Ros L., Mellado E., Rodriguez-Tudela J.L. 2011. Antifungal Slovania number of currently recognized hypervirulent genotypes (e.g. 027) but has studied susceptibility profile of clinical Alternaria spp. identified by molecular methods. J. "One of the different types of unrelated strains with either high virulence (isolated from severe Antimicrob. Chemother. 66: 2585-2587. advantages of cases) or high endemic potential (widespread worldwide or nationwide). Comparative  Alanio A., Beretti J.L., Dauphin B., Mellado E., Quesne G., Lacroix C., Amara A., Berche P., this framework genomic and transcriptomic approaches showed that both groups (high virulence Nassif X., Bougnoux ME. 2011. Matrix-assisted laser desorption ionization time-of-flight is that the and high endemic potential) differ from each other when compared to the selected mass spectrometry for fast and accurate identification of clinically relevant Aspergillus paperwork controls in the presence or absence of the genes and in the expression levels of species. Clin. Microbiol. Infect. 17: 750-755. part is short the genes. Project results suggest that sporulation does not seem to be important and simple.  Monteiro M.C., de la Cruz M., Cantizani J., Moreno C., Tormo J.R., Mellado E., de Lucas for colonization in the mouse model. Also, new unique spore protein with putative -Also, the status J.R., Asensio F., Valiante V., Brakhage A.A., Latgé J.P., Genilloud O., Vicente F. 2012. A seminars are function in spore structure and germination was identified. new approach to drug discovery: high-throughput screening of microbial natural very beneficial Part of the project was contribution to development of web based tool for C. difficile extracts against Aspergillus fumigatus using resazurin. Journal Biomolecular Screening because ribotyping data analysis (WEBRIBO; http://webribo.ages.at) that for the first time 17: 542-549. they involve enables easy assignment of ribotype and interlaboratory comparisons.  Horn F., Heinekamp T., Kniemeyer O., Pollmächer J., Valiante V., Brakhage A.A. 2012. a relatively Publications related to the funded project: Systems biology of fungal infection. Frontiers in Microbiology 3:118. small, but  Rupnik M, Wilcox MH, Gerding DN. (2009) Clostridium difficile infection: new  Müller S., Baldin B., Groth M., Guthke R., Kniemeyer O., Brakhage A.A., and Valiante very diverse, developments in epidemiology and pathogenesis. Nat Rev Microbiol. 7(7):526-36. V. Comparison of transcriptome technologies in the pathogenic fungus Aspergillus group of Rupnik M. (2010) Clostridium difficile : (re)emergence of zoonotic potential. Clin. fumigatus reveals novel insights in genome structure and MpkA-dependent gene scientists, from Infect. Dis., 51: 583-584. expression. BMC Genomics, submitted. complementary  Barbut F., Jones G., Eckert C. (2011) Epidemiology and control of Clostridium difficile fields." infections in healthcare settings : an update. Current Opinion in Infectious Diseases Curr Opin Infect Dis. 24(4):370-6.  Monot, M., Boursaux-Eude, C., Thibonnier, M., Moszer, I., Vallenet, D., Medigue, C., Martin-Verstraete, I. and B. Dupuy. (2011) Re-annotation of the genome sequence of Clostridium difficile strain 630. J. Med Microbiol., 60:1193-9.  Carter GP, Douce GR, Govind R, Howarth PM, Mackin KE, Spencer J, Buckley AM, Antunes A, Kotsanas D, Jenkin GA, Dupuy B, Rood JI, Lyras D. (2011) The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile. PLoS Pathog., 7 (10):e1002317.  Saujet L, Monot M, Dupuy B, Soutourina O, Martin-Verstraete I. (2011) The key sigma factor of transition phase, SigH, controls sporulation, metabolism, and virulence factor expression in Clostridium difficile. J Bacteriol.,193(13):3186-96. |68 69 |

 Barbut F, Monot M, Rousseau A, Cavelot S, Simon T, Burghoffer B, Lalande V, Tankovic Project name: Transcriptome-based Monitoring and Eradication of Chronic Chlamydial J, Petit JC, Dupuy B, Eckert C. (2011) Rapid diagnosis of Clostridium difficile infection by Infection (Acronym: ChlamyTrans) multiplex real-time PCR. Eur J Clin Microbiol Infect Dis., 30 (10):1279-85. Coordinator: Matthias Maass, Institute of Medical Microbiology, Hygiene and Infectious  Janezic S, Indra A, Allerberger F, Rupnik M. (2011) Use of different molecular typing Diseases, University Hospital Salzburg, Salzburg, Austria methods for the study of heterogeneity within Clostridium difficile toxinotypes V and Unable to add his photo III. J Med Microbiol., 60(Pt 8):1101-7. Partners: Kamil Önder, Procomcure GmbH, Salzburg, Austria  Janezic S, Strumbelj I, Rupnik M. (2011) Use of modified PCR ribotyping for direct Mirja Puolakkainen, Haartman Institute, Department of Virology, University detection of Clostridium difficile ribotypes in stool samples. J Clin Microbiol., 49 of Helsinki, Finland (8):3024-5 Dezső Peter Virók, Institute for Plant Genomics, Human Biotechnology and Bioenergy  Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, Monnet (BAY-GEN), Szeged, Hungary DL, van Dissel JT, Kuijper EJ; ECDIS Study Group. (2011) Clostridium difficile infection in Abstract: ChlamyTrans is a consortium of a commercial partner and three research Europe: a hospital-based survey. Lancet, 377 (9759):63-73. groups that integrates expertises in trancriptomics and the pathogenomics of  Pecavar V., Blaschitz M., Hufnagl P., Zeinzinger J., Fiedler A., Allerberger F., Maass M., chronic disease with the intracellular pathogen Chlamydia. ChlamyTrans uses data Indra A. (2012) High Resolution Melting Analysis of the single nucleotide polymorphism from two complementary genome-wide transcriptomics approaches to identify hot spot region in the rpoB gene as indicator of reduced susceptibility for Rifaximin in diagnostic tools and drug targets for monitoring and eradicating chlamydial Clostridium difficile J Med Microbiol., 61(Pt 6):780-5. infections. Base is to construct cloned ORFs of C. trachomatis and C. pneumoniae  Monot M., Orgeur M., Camiade E., Brehier C., Dupuy B. (2012) COV2HTML: a visualization and to identify interfering peptides for deriving therapeutic small molecule and analysis tool of Bacterial NGS data for biologists (in submission). inhibitors via a high-throughput platform. In the complementary approach, in vivo  Pereira, F.C., L. Saujet, E. Couture-Tosi, T. dos Vultos, S. Hoys, C. Janoir, I. Martin- genome-wide transcriptional profiling delivers a definition of the highly expressed Verstraete, B. Dupuy and A. O. Henriques. (2012) Morphodynamics of sporulation in chlamydial genes needed for survival of the persistent state and maintenance of Clostridium difficile (in preparation). chronic infection. Both approaches deliver potential drug target proteins, infection  Pereira, F.C., T. dos Vultos, E. Couture-Tosi, L. Saujet, M. Monot, S. Hoys, C. Janoir, I. markers and inhibitory peptides for validation of clinical and diagnostic relevance Martin-Verstraete, B. Dupuy, and A. O. Henriques. (2012) A protein required for host in established models of chlamydial infection. Current achievements are: C. colonization by Clostridium difficile is a key determinant for the assembly of the spore pneumoniae and C. trachomatis transcriptomes have been fully obtained, the outer surface layer (in preparation). complete gene-collectionbeing available as pure DNA and in expression vectors for synthesis as GST fusion proteins; A genotyping method for C. trachomatis was developed; Recovery of chlamydial RNA from patient samples was optimized. A subtranscriptome amplification method was developed. Publications related to the funded project:  Kari L, Goheen MM, Randall LB, Taylor LD, Carlson JH, Whitmire WM, Virok D, Rajaram K, Endresz V, McClarty G, Nelson DE, Caldwell HD.Generation of targeted Chlamydia trachomatis null mutants. Proc Natl Acad Sci U S A. 2011;108:7189-93.  Burian K, Endresz V, Deak J, Kormanyos Z, Pal A, Nelson D, Virok DP. Transcriptome analysis indicates an enhanced activation of adaptive and innate immunity by chlamydia-infected murine epithelial cells treated with interferon-. J Infect Dis. 2010;202:1405-14.  Balogh EP, Faludi I, Virók DP, Endrész V, Burián K. Chlamydophila pneumoniae induces production of the defensin- like MIG/CXCL9, which has in vitro antichlamydial activity. Int J Med Microbiol. 2011;301:252-9.  Maass V, Kern JM, Poeckl M, Maass M. Sequence homologies between Mycoplasma and Chlamydia spp. lead to false-positive results in chlamydial cell cultures tested for mycoplasma contamination with a commercial PCR assay. J Clin Microbiol. 2011;49:3681-2  Keurulainen L, Salin O, Siiskonen A, Kern JM, Alvesalo J, Kiuru P, Maass M, Yli- Kauhaluoma J, Vuorela P. Design and synthesis of 2- arylbenzimidazoles and |70 71 |

evaluation of their inhibitory effect against Chlamydia pneumoniae. J Med Chem. Project name: Mechanisms and modulation of innate immune responses to Streptococcus 2010;53:7664-74. pneumoniae and Streptococcus pyogenes (Acronym: StreptoMics)  Salin O, Alakurtti S, Pohjala L, Siiskonen A, Maass V, Maass M, Yli- Kauhaluoma Coordinator: Pavel Kovarik, Max F. Perutz Laboratories, University of Vienna, Austria J, Vuorela P. Inhibitory effect of the natural product betulin and its derivatives Partners: Emmanuelle Charpentier, University of Umea, Sweden against the intracellular bacterium Chlamydia pneumoniae. Biochem Pharmacol. Ilkka Julkunen, National Institute for Health and Welfare, Helsinki, Finland 2010;80:1141-51. Sylvia Knapp, Medical University of Vienna, Center of Molecular Medicine, Vienna, Austria  Törmäkangas L, Markkula E, Lounatmaa K, Puolakkainen M. Chlamydia pneumoniae Claire Poyart, Université Paris Descartes, National Centre for Streptococci, Paris, France infection in polarized epithelial cell lines. Infect Immun 78:2714-22;2010. Intercell AG, Vienna, Austria  Mannonen L, Markkula E, Puolakkainen M. Analysis of Chlamydia pneumoniae Abstract: Streptococcus pyogenes and Streptococcus pneumoniae are the most infection in mononuclear cells by reverse transcription- PCR targeted to chlamydial frequently found bacterial pathogens in patients with respiratory infections. The innate gene transcripts. Med Microbiol Immunol, 200(3):143-54;2011. immune system plays a key role in recognition of these pathogens and in launching  Niemi S, Hiltunen-Back E, Puolakkainen M. Chlamydia trachomatis Genotypes and the immune response. The aims of the project were 1) to identify the pathogen- the Swedish New Variant among Urogenital Chlamydia trachomatis Strains in associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) Finland. Inf Dis Obstet Gyn, 2011:481890. involved recognition of these pathogens by the innate immune cells, 2) to elucidate  Niemi SJ, Greub G, Puolakkainen M. Chlamydia-related bacteria in respiratory the mechanism of innate immune responses and 3) to test modulation of the innate samples in Finland. Microbes Infect 13(10):824-7;2011b immune responses as a possibility for therapeutic intervention in animal models. We  Campbell LA, Puolakkainen M, Lee A, Rosenfeld M, Garrigues HJ, Kuo CC. Chlamydia found that upon phagocytosis S. pyogenes induces type I interferons (IFNs) in innate pneumoniae binds to the lectin-like oxidized LDL receptor for infection of endothelial immune cells and that this cytokine is required for successful defense. Experiments cells. Microbes and Infection, in press 2011. addressing the therapeutic administration of this cytokine and of modulators of  Korhonen JT, Puolakkainen M, Häivälä R, Penttilä T, Haveri A, Markkula E, and phagocytosis in models of S. pyogenes infections are in progress. Activation of the Lahesmaa R. Flotillin-1/reggie-2 contributes to Chlamydia pneumoniae growth innate immune system by S. pyogenes was analyzed using 1) clinical isolates collected and associates with bacterial inclusion. Infect Immun. 2012;80:1072-8. in 1998 – 2009 by the French CNR and 2) a transposon library generated in the course  Korhonen JT, Puolakkainen M, Haveri A, Tammiruusu A, Sarvas M, Lahesmaa of the project. We identified the S. pyogenes-derived RNA as a major PAMP that is R. Chlamydia pneumoniae entry into epithelial cells by clathrin-independent required for IFN production and immune response. endocytosis. Microb Pathog. 2012;52:157-64. Publications related to the funded project:  Radvan M, Stiefvater R, Grunert T, Sharif O, Miller I, Marchetti-Deschmann M, Allmaier G, Gmeiner M, Knapp S, Kovarik P, Müller M, Strobl B. Tyrosine kinase 2 controls interleukin-1beta production at the translational level. J Immunol 185:3544-3553 (2010).  Nina Gratz, Harald Hartweger, Ulrich Matt, Franz Kratochvill, Marton Janos, Stefanie Sigel, Barbara Drobits, Xiao-Dong Li, Sylvia Knapp, Pavel Kovarik. Type I interferon production induced by Streptococcus pyogenes-derived nucleic acids is required  for host protection. PLoS Pathog 7:e1001345 (2011) |72 73 |

Project name: Pathogen-host metabolomics and interactomics (Acronym: PATHOMICS) Project name: Development, prevention and early diagnostic detection of Clostridium Coordinator: Thomas Rattei, Technische Universität München, Germany difficile-associated colitis – an interdisciplinary network (Acronym: METAGUT) Partners: Dmitrij Frishman, Technische Universität München, Germany; Philippe Schmitt- Coordinator: Stephan J. Ott, Clinic for Internal Medicine I, University-Hospital Schleswig- Kopplin, Karsten Suhre, Helmholtz Center Munich, Germany Holstein (UKSH), Campus Kiel, Kiel, Germany Johannes Hegemann, Universität Düsseldorf, Germany Partners: Vitor A. P. Martins dos Santos, Laboratory of Systems and Synthetic Biology, Jan Rupp, Universität Lübeck, Germany University Wageningen, Wageningen, The Netherlands Matthias Horn, University of Vienna, Austria; Giulio Superti-Furga, Center for Molecular Manuel Ferrer, Institute of Catalysis, CSIC, Campus UAM-Cantoblanco, Madrid, Spain Medicine Vienna, Austria Andres Moya, Cavanilles Institute on Biodiversity and Evolutionary BiologyUniversity of Agathe Subtil, Institut Pasteur Paris, France Valencia, Valencia, Spain Romé Voulhoux, Laboratoire d›Ingénierie des Systèmes Macromoléculaires Laia Pedrola, Life Sequencing S.A., Valencia, Spain Marseille, France Christoph Reschreiter, Bernard Ronacher, Anagnostics Bioanalysis GmbH, St. Valentin, Ana Conesa, Centro de Investigaciones Príncipe Felipe Valencia, Spain Austria Abstract: Bacterial protein secretion represents a key mechanism for infection and Miguel Godinho, Lifewizz Lda, Porto, Portugal pathogenesis and enables the modulation of infected hosts by pathogenic bacteria. The Abstract: Pseudomembranous colitis (PMC) is an infectious disease of the human colon diagnostic and therapeutic potential of this process is not limited to the secretion machineries caused by Clostridium difficile. The disease is characterized by diarrhea, fever and abdominal and the segregated proteins themselves, but includes the largely unknown effects of these pain. A main factor underlying the development of pseudomembranous colitis is the use of proteins on the host cells. To exploit this potential, we focus on the systematic and integrative broad-spectrum antibiotics, such as clindamicin or cephalosporins, which lead to an altered investigation of the host-pathogen protein-protein interactomes of human pathogens and Gerhad Braus, intestinal microflora allowing Clostridium difficile bacteria to be activated or overgrow. The their influence on the metabolic system of the host cells. Germany colitis itself is caused by special toxins of Clostridium difficile (toxin A, B). The diagnostic In this project, we develop novel biomarkers and drug target candidates for the diagnosis "For me the tests are based on both the culture of the bacterium and the detection of toxin A. In addition and therapy of two different classes of pathogenic bacteria, sharing a common principle main advantage to the obvious burden to the many individual patients, PMC generates tremendous costs of host-pathogen interaction: the secretion of effector proteins into their host cells. of being part in the health systems of most of the industrialized countries. Diagnosis and treatment Pseudomonas aeruginosa is a gram-negative bacterium and an opportunistic human of the ERA-NET of pseudomebranous colitis are laid down in clinical guidelines and are backed by clinical pathogen that causes severe infections in immune compromised individuals. Chlamydiae PathoGenoMics randomized studies, but little is known about the development of the disease. In PMC, are gram-negative bacteria and obligate intracellular human pathogens, causing a broad consortium it is hypothesized that alterations of the composition of the intestinal microflora lead to spectrum of diseases like trachoma, sexually transmitted disease, infertility and community- is that you competition of microorganisms for space and nutrients. Revealingly, probiotic preparations acquired pneumonia. Due to the high incidence of Chlamydiae and P. aeruginosa infections, can enter a seem to be effective in the prevention and of pseudomembranous colitis. However, as yet, improvements in diagnostics and therapy based on the results of this project will be of scientific field there is no clear concept about the pathophysiology and pathogenesis of pseudoembranous that is possible major importance for human health. colitis, nor a through understanding of the mechanisms and interactions this serious only as a Publications related to the funded project: group". disease. The project aims at a) generating insights into the onset and development of  Alphonse et al., J. Struct. Biol. 2010 Clostridium difficile-associated pseudomembranous colitis and of its relation to (altered) gut  Arnold et al., Microbes Infect. 2010 microflora in humans, and b) translating this knowledge into strategies for early diagnosis  Bleves et al., Int. J. Med. Microbiol. 2010 and prevention. This will be done through an integrated approach whereby the composition  Conesa et al., Chemom. Int. lab. Syst. 2010 and metabolic status of the gut microbiome of healthy individuals and from patients with  Dehoux et al., BMC Genomics 2011 broad-spectrum antibiotic therapy and pseudomembranous colitis will be thoroughly  Dietz et al., Der Mikrobiologe 2011 characterized and compared. The composition of the intestinal microflora (16S-based)  Dietz et al., Microbes Infect 2012 before, during and after manifestation of colitis has been determined in patient materials.  Garcia-Alcalde, Bioinformatics 2011 The (pyro-) sequencing of selected metagenomes of healthy individuals and patients with  Jehl et al., NAR 2011 broad spectrum antibiotic therapy and pseudomembranous colitis at different stages  Nuk et al., 2011 of disease, coupled to the in-depth analysis of the metabolic profiling through a high-  Lang et al., Mol. Microbiol. 2010 throughput array screening method, meta-proteomics and meta-transcriptomics, and  Roth et al., PNAS 2010 assisted by a comprehensive bioinformatics analysis and reverse engineering of the high-  Salacha et al., Environ. Microbiol. 2010 throughput information produced, will provide compositional and functional signatures  Szaszák et al., PLoS Pathogens 2011 associated to pseudomembranous colitis. First analysis indicates that broad-spectrum antibiotic therapy leads to dynamic changes in microbial composition in patients compared |74 75 |

and controls. In contrast to controls, the marked reduction of diversity and species richness manganese reconstituted ribonucleotide reductase from . J Biol Chem. of the gut microbiota in patients, during antibiotic therapy seems to be a risk factor in the 286:33053-33060. development of PCM.  Denizot J, Sivignon A, Barreau F, Darcha C, Chan HF, Stanners CP, Hofman P, Darfeuille- Publications related to the funded project: Michaud A, Barnich N. (2012). Adherent-invasive Escherichia coli induce claudin-2  María José Gosalbes, Anette Friedrichs, Ana Elena Pérez-Cobas, Henrik Knecht, Alejandro expression and barrier defect in CEABAC10 mice and Crohn›s disease patients. Inflamm Artacho, Kathleen Eismann, Wolfgang Otto, David Rojo, Rafael Bargiela, Martin von Bowel Dis. 18:294-304. Bergen, Vitor dos Santos, Sven C Neulinger, Carolin Däumer, Amparo Latorre, Coral  Johansson R, Torrents E, Lundin D, Sprenger J, Sahlin M, Sjöberg BM, Logan DT (2010). Barbas, Jana Seifert, Stephan J Ott, Manuel Ferrer, Andrés Moya. High-resolution crystal structures of the flavoprotein NrdI in oxidized and reduced Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. states – an unusual flavodoxin. FEBS Journal. 277:4254-4277. Submitted to Plos Biology 06/2012  Lundin D, Gribaldo S, Torrents E, Sjöberg BM, Poole AM. (2010). Ribonucleotide reduction –horizontal transfer of a required function spans all three domains. BMC Evol Biol. 10:383. Project name: Identification of hot spots of divergence and rapidly changing genes within  Lundin D, Torrents E, Poole AM, Sjoberg BM. (2009). RNRdb, a curated database of the Shiga toxin-producing Escherichia coli (Acronym n.a.) universal enzyme family ribonucleotide reductase, reveals a high level of misannotation Coordinator: Alexander Mellmann, Institute of Hygiene, University Hospital Muenster, in sequences deposited to Genbank. BMC Genomics. 10:589. Muenster, Germany  Miquel S, Claret L, Bonnet R, Dorboz I, Barnich N, Darfeuille-Michaud A. (2010). Role of Partners: Nicolas Barnich, Université d’Auvergne, Clermont-Ferrand, France, decreased levels of Fis histone-like protein in Crohn›s disease-associated adherent Dorothea Orth, Department of Hygiene, Microbiology and Social Medicine, Innsbruck, Austria invasive Escherichia coli LF82 bacteria interacting with intestinal epithelial cells. J Eduard Torrents, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Bacteriol, 192:1832-1843. Abstract: Escherichia coli is the predominant nonpathogenic facultative flora of the human  Orth D, Ehrlenbach S, Brockmeyer J, Khan AB, Huber G, Karch H, Sarg B, Lindner H, intestine. Some E. coli strains have acquired specific virulence factors, which led to an Würzner R. (2010) EspP, a serine protease of enterohemorrhagic Escherichia coli, impairs increased ability of the bacteria to adapt to new niches and allow them to cause a broad complement activation by cleaving complement factors C3/3b and C5. Infect Immun. spectrum of diseases such as of the gastrointestinal, urinary, or central nervous system 78: 4294-4301. in the human hosts. This project focused on Shiga toxin-producing E. coli (STEC) and on  Sjöberg BM, Torrents E. (2011). Shift in ribonucleotide reductase gene expression in Adherent-Invasive E. coli (AIEC), two intestinal pathogenic subgroups of E. coli. In four Pseudomonas aeruginosa during infection. Infect Immun. 79:2663-2669. different workpackages, well-defined collections of STEC strains isolated from humans and  Torrents E, Sjöberg BM. (2010). Antibacterial activity of radical scavengers against class the environment and AIEC strains from human infections were investigated. Starting from Ib ribonucleotide reductase from Bacillus anthracis. Biol Chem. 391:229-234 molecular typing, novel SNP schemes were developed and expanded using whole genome sequencing, which helped to further characterize rapidly evolving regions. Furthermore, global transcriptional changes were studied. Especially the expression and regulation of the nrd gene, which encodes for the ribonucleotide reductase, were investigated to determine its role in pathogenesis. Finally the detected variations were also functionally analyzed to confirm their functional impact. Together, this led to a deeper understanding of the pathogenesis and to improvement of diagnosis and typing. In future, our data will help to establish new preventive and therapeutic approaches. Publications related to the funded project:  Bielaszewska M, Middendorf B, Tarr PI, Zhang W, Prager R, Aldick T, Dobrindt U, Karch H, Mellmann A. (2011) Chromosomal instability in enterohaemorrhagic Escherichia coli O157:H7: impact on adherence, tellurite resistance and colony phenotype. Mol Microbiol. 79:1024-1044.  Creuzburg K, Middendorf B, Mellmann A, Martaler T, Holz C, Fruth A, Karch H, Schmidt H. (2011) Evolutionary analysis and distribution of type III effector genes in pathogenic Escherichia coli from human, animal and food sources. Environ Microbiol. 13:439-452.  Crona M, Torrents E, Rohr AS, Hofer A, Furrer E, Tomter AB, Andersson KK, Sahlin M, Sjöberg BM. (2011). NrdH-Redoxin protein mediates high enzyme activity in |76 77 |

Third Call for Proposals: Name Institution/company The announcement for the third transnational call for project proposals within the ERA- Centro Nacional de Biotecnología – CSIC Madrid, NET PathoGenoMics was under the heading, “Translational pathogenomics: the prevention, Prof. Dr. José Luis Martínez Spain diagnosis, treatment and monitoring of infectious diseases in humans.” Out of 50 pre- proposals, a total of 23 full proposals were received, of which nine projects were selected. The list of micro-organisms studied under the third call was more varied and extensive U1001 INSERM Faculté de Médecine Paris Prof. Dr. Ivan Matic than in the previous two calls. As was the case with the second call, applicants were Descartes. Université Paris Descartes Paris, France required to partner with health care institutions and/or industry.

Members of the Scientific Advisory Board (SAB) of the third call: Institute of Medical Microbiology and Diagnostic Prof. Dr. Erzsebet Nagy University of Szeged Szeged, Hungary Name Institution/company

Faculty of Medicine, Tel Aviv University, Ramat Aviv, Dr. Nir Osherov Prof. Dr.Wolf-Dietrich Hard, ETH Zürich, Institut für Mikrobiologie Zürich, Israel Chair Switzerland

Department of Molecular Genetics Weizmann Fundation Caubet – Cimera International Center for Prof. Dr. Rotem Sorek Prof. Dr. José Antonio Institute of Science, Rehovot, Israel Advanced Respiratory Medicine Recinte Hospital Bengoechea Joan March Bunyola, Mallorca, Spain Projects funded:

Prof. Dr. Hillel Bercovier Hebrew University of Jerusalem, Jerusalem, Israel Title Project Leader/ Project Partners Coordinator

Prof. Dr. Gad Frankel Imperial College London, London, UK A genome-wide approach for Matthias Wilmanns, DE characterizing the mode of Marc A. Marti- LLuís Ballell, ES action of novel compounds Renom, ES Olivier Neyrolles, FR against Tuberculosis (GeMoA) Brigitte Gicquel, FR Institut für Hygiene und Mikrobiologie Universität Prof. Matthias Frosch Würzburg, Würzburg, Germany

Pascale Romby, FR Global analysis of antisense Francois Vandenesh, FR regulatory mechanisms School of Medical Sciences, Institute of Medical Iñigo Lasa, ES Cecilia Arraiano/ Prof. Dr. Neil Gow in Staphylococcus aureus Sciences University of Aberdeen, Aberdeen, UK Susana Domingues, PT (ARMSA) José R. Penadés, ES

Department of Microbiology, Moyne Institute Prof. Dr. Jay Hinton of Preventive Medicine, School of Genetics and Microbiology, Trinity College, Dublin, Ireland Biomarkers for prevention, Juan Sainz Perez, ES diagnosis and response Herrmann Einsele, Jean Paul Latgé, FR to therapy of invasive DE Javier Yuguerros Marcos, FR aspergillosis (AspBIOmics) Cornelia Lass-Floerl, AT Dr. Khalid Islam KI Consulting Reinach, Switzerland

Understanding colonisation and the transition to Laboratoire d’Immunologie-Microbiologie, Unité de pathogenic dissemination by Christophe d’Enfert, FR Recherche en Biologie Moléculaire (URBM) Facultés Attila Gacser, HU Prof. Dr. Jean-Jacques Letesson Candida species; towards early Uwe Groß, DE Bernhard Hube, DE Universitaires Notre-Dame de la Paix Namur, diagnostic and therapeutic Belgium approaches (CANDICOL) |78 79 |

Title Project Leader/ Project Partners All the following project abstracts were written by the project coordinators who are solely Coordinator responsible for their content Project name: A genome-wide approach for characterizing the mode of action of novel Human fungal pathogens compounds against Tuberculosis (Acronym: GeMoA) under oxygen stress; adaptive Jesus Pla, ES Coordinator: Marc A. Marti-Renom, National Center for Genomic Analysis (CNAG) & Center mechanisms to hypoxia Axel Brakhage, DE Joachim F. Ernst, and reactive oxygen species Enrique Herrero, ES for Genomic Regulation (CRG), Barcelona, Spain DE and their consequences for Cornelia Lass-Flörl, AT Partners: Matthias Wilmanns, EMBL-Hamburg, Germany host interaction and therapy Christian Leggewie, DE LLuís Ballell, GSK-TCMDC, Madrid, Spain (OXYstress) Olivier Neyrolles, IPBS/CNRS, Toulouse, France Brigitte Gicquel, Institut Pasteur, Paris, France Characterisation of host cell Abstract: One third of the world›s overall population is infected with Mycobacterium João Paulo Gomes, PT pathways altered by effectors Anja Lührmann, DE tuberculosis (Mtb), the causing agent of Tuberculosis (TB). About 95% of those, are thought to be of Brucella, Chlamydia and Luís Jaime Mota, Carmen Plasencia, ES Coxiella: identification of PT in latent infection where Mtb rarely replicates. Nevertheless, ~10% of latent infections eventually Isabel Rodriguez-Escudero, ES novel therapeutic targets Suzana Salcedo, FR progresses to active disease, which, if left untreated, kills more than half of the infected (CELLPATH) patients. Mtb infection is best described as an equilibrium involving a balance of activation and suppression of host responses, orchestrated by a complex and dynamic series of interactions between multiple host and bacterial components. Therefore, it is not unsurprising that single- Impact of mobile genetic Philippe Glaser, FR target approaches for the identification of lead compounds, followed by establishment of elements and horizontal gene Ulrich Dobrindt, DE Carmen transfer on bacteria-host Sören Schubert, DE pipelines for drug discovery, have had limited success. To address such limitation, we plan to Buchreiser, FR adaptation: a genomics view Joachim Reidl, AT apply genome-wide approaches to characterize the mode-of-action of a compound library, (MobileGenomics) Tamara Smokvina, FR which has been validated for its activity against Mtb by GlaxoSmithKline (GSK, Partner 3), a major player in the pharmaceutical industry. Our approach uses an alternative and highly promising route by starting rather than finishing an initial process for lead compound Ivo G. Boneca, FR Helicobacter pylori diversity José Carlos Machado/ characterization. in pathogenesis, antibiotic Ceu Figueiredo, PT resistance and evasion Sebastian. Publications related to the funded project: Christine Josenhans, DE from natural and vaccine- Suerbaum, DE Rainer Haas, DE  Feuerriegel, I., Köser, C., Baù, D., Rüsch-Gerdes, S., Summers, D., Archer, J., Marti-Renom, induced immune responses Peter Maltertheiner/ (HELDIVPAT) M.A. and Niemann, S. “Impact of fgd1 and ddn diversity in Mycobacterium tuberculosis Thomas Wex, DE complex on in vitro susceptibility to PA-824” Antimicrobial Agents and Chemotherapy (2011) 55 5718-5722 Pascale Cossart /  Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. “Mycobacterium abscessus: a new Analysis of the cellular Marc Lecuit, FR antibiotic nightmare”. J Antimicrob Chemother. 2012 Apr;67(4):810-8. Epub 2012 Jan 30. mechanisms underlying the Uwe Kärst / Lothar Jänsch, DE Trinad early response of the host Francisco García-del Portillo, ES Chakraborty, DE to stress induced by Listeria Didier Cabanes, PT infection (LISTRESS) Yair Aharonowitz / Anat A. Herskovits, IL |80 81 |

Project name: Global analysis of antisense regulatory mechanisms in Staphylococcus aureus Project name: Invasive aspergillosis: Biomarkers for prevention, diagnosis and treatment (Acronym: ARMSA) response (Acronym: aspBIOmics) Coordinator: Iñigo Lasa, Instituto de Agrobiotecnología. Universidad Pública de Navarra, Coordinator: Hermann Einsele, Universitätsklinikum Würzburg (UKW), Germany Navarra, Spain Partners: Cornelia Lass Floerl, Medizinische Universität Innsbruck (MUI), Austria Partners: Pascale Romby,Université De Strasbourg, Strasbourg, France Jean Paul Latgé, Institute Pasteur, Paris, France Francois Vandenesh,Faculté de Médecine RTH LaennecINSERM , Lyon cedex, France Juan Sainz Perez, University of Granada (AHPS), Spain Cecilia Arraiano/Susana Domingues,Instituto de Tecnologia Quimica e BiologicaUniversidade Javier Yuguerros Marcos, Biomerieux (bMx), France Nova de Lisboa, Lisbon, Portugal Abstract: Invasive aspergillosis (IA) is the most common cause of mortality in patients being José R. Penadés, Centro Investigación y Tecnología Animal, Segorbe, Castellón, Spain treated for haematological malignancies. Although, IA may be perceived to be an uncommon Abstract: Global analysis of antisense regulatory mechanisms in Staphylococcus aureus disease, with an incidence of 10,000 patients annually in Europe, there is increasing evidence (ARMSA) Abstract The project aims at investigating the impact of antisense regulatory that IA is affecting a broader range of patients. IA is the most expensive opportunistic mechanisms in the major human pathogen Staphylococcus aureus. The major achievements infection in immunosuppressed patients; the annual cost in Europe is >100 million Euro. of the consortia during this first year have been: 1. The transcriptome map of S. aureus A major problem in the management of IA is the poor diagnosis. Within aspBIOmics, has been completed. It contains 2912 transcripts, including 1554 mRNAs, 218 small non- we develop and evaluate a battery of in vitro assays for a comprehensive multimodality coding RNAS and 1140 antisense RNAs. It also includes several overlapping transcrips (71 analysis, combining the detection of Aspergillus elements (RNA, polysaccharides, proteins), 5’ UTRs and 263 3’ UTRs). In line with our hypothesis, the transcriptome map also revealed host factors including cytokine profiles, and the individual genetic susceptibility of the a massive antisense transcription process that affect at least to 50% of the transcripts. 2. host. The advance will be the availability of a panel of biomarkers incorporated into rapid The transcriptome maps of isogenic mutants in ribonucleases (RNaseIII and Pnp) and sigma and sensitive ex vivo assays. This is the first time that a combined multi-parameter B transcription factor have been compared with that of the wildtype strain. The results diagnostic strategy is undertaken to target aspergillosis This strategy has the potential to have uncovered the existence of a mechanism of digestion of overlapping transcripts by identify patients who are at highest risk of IA before the infection occurs so that tailored RNaseIII enzyme. As a consequence of this cleavage activity, the transcriptome contains a prophylaxis can be given, and in patients who have established IA to monitor the success collection of short (20 nucleotides in average) RNA molecules that accumulates in similar of antifungal therapy and the outcome of the infection. (www.aspbiomics.eu) amounts in every region where overlapping transcription occurs. Our results also revealed Publications related to the funded project: that the activity of Pnp enzyme is not required for this process3. The transcriptome map  Mithun Das Gupta, Jan Springer, Tanja Breitschopf, Hannes Schlossnagel, Helga of S. aureus during phage and PI replication has been analysed using tiling arrays. Several Sennefelder, Anna-Lena Schmitt, Oliver Kurzai, Kerstin Huenniger, Hermann Einsele, genes whose expression is affected after SOS induction, by the presence or absence of a Juergen Loeffler (2012) Aspergillus fumigatus induces microRNA-155 expression in vitro phage or a SaPI, or by induction of the SaPI cycle have been identified. The role of some in human monocyte-derived dendritic cells. PLoS ONE, in revision of these genes during the replication of these mobile elements is currently under study4. Deletion mutant strains of four small RNA (RsaA, RsaE, RsaG and RsaH) in three different genetic backgrounds of S. aureus (RN6390, HG001, Newman) have been successfully generated. Analysis of the phenotypes associated to each small RNA reveal that RsaA is involved in biofilm and capsule formation whereas RsaG seems to be involved in fructose metabolism. Publications related to the funded project:  Felden B, Vandenesch F, Bouloc P & Romby P (2011) The Staphylococcus aureus RNome and its commitment to virulence. PloS Pathogen 7: e1002006  Jester B., Romby P. & Lioliou E. (2012) International Journal of Microbiology, 2012;2012:592196.  Lasa I, Alejandro Toledo-Arana A, Dobin A, Villanueva M, Ruiz de los Mozos I, Vergara- Irigaray M, Segura V, Fagegaltier D, Penadés JR, Valle J, Solano C y Gingeras TR. (2011) Genome-wide antisense transcription drives mRNA processing in bacteria. Proc. Natl. Acad. Sci. USA 108, 20172-20177  Lioliou, E., Romilly, C., Geissmann, T., Vandenesch, F. and Romby, P. (2012) RNA-mediated regulation of virulence gene expression : another layer of complexity ». In « Bacterial Regulation Network » (eds. Filloux, A.), Horizon Scientific Press, Norwich UK, in press. |82 83 |

Project name:Understanding colonisation and the transition to dissemination by Candida Project name: Human fungal pathogens under oxygen stress: adaptive mechanisms to species: towards early diagnostic and therapeutic approaches (Acronym: CandiCol) hypoxia and reactive oxygen species and their consequences for host interaction and therapy Coordinator: Attila Gacser, University of Szeged, Faculty of Science and Informatics, (Acronym: OXYstress) Department of Microbiology, Szeged , Hungary Coordinator: Joachim F. Ernst, Univ. Duesseldorf, Molecular Mycology, Duesseldorf, Germany Partners: Christophe d›Enfert, Institut Pasteur ; Unité Biologie et Pathogénicité Fongi ues Partners: Jesus Pla, Univ. Complutense de Madrid, Dept. of Microbiology II, Madrid, Spain – INRA, Paris, France Axel Brakhage, Leibniz Institute, Molecular and Applied Microbiology, Jena, Germany Uwe Groß, University Medical Center Go ttingen, Institute for Medical Microbiology, German Enrique Herrero, Univ. Lleida, Dept. de Ciencies Mediques Basiques, Lleida, Spain National Reference Center for Systemic Mycoses Kreuzbergring Go ttingen, Germany Cornelia Lass-Flörl, Innsbruck Medical University, Hygiene and Medical Microbiology, Bernhard Hube,Department of Microbial Pathogenicity Mechanisms, Leibniz Institute Innsbruck, Austria Natural Product Research & Infection Biology, Jena, Germany Christian Leggewie, evocatal GmbH, Duesseldorf, Germany Abstract: Candida albicans (Ca), Candida glabrata (Cg) and Candida parapsilosis (Cp) are Abstract: The OXYstress project investigates and exploits the fact that invasive pathogens the three main yeast species that are both commensal of humans and responsible for frequently interact with the human host in niches low in oxygen, often associated with devastating disseminated infections. The aim of this project is to identify the attributes increased levels of reactive oxygen species and carbon dioxide. Such conditions are that are shared by or distinguish these three species and contribute to the transition from rarely taken into account in current models of infection and assessment of antifungal commensalism to dissemination. To this aim, we will establish or further develop ex vivo sensitivities. The most important human fungal pathogens Candida albicans and and in vivo models to study host colonisation and systemic infections by Ca, Cg or Cp. Aspergillus fumigatus, as well as emerging zygomycetes pathogens, cause life-threatening Using these models, we will identify fungal and host transcriptional patterns and fungal systemic infections, during which they encounter and adapt to numerous hypoxic niches antigens associated with pathological colonisation or bloodstream infection. Furthermore, within tissues, organs and cells. The project unites an international panel of experts by developing novel mutant strain collections (gain- and loss-of-function), we will identify including academic researchers, a clinical scientist and a company to clarify and exploit sets of fungal genes crucial for colonisation and/or dissemination. We expect to develop the molecular mechanisms of fungal responses and host interactions under oxygen stress novel diagnostic tools of translational value for discriminating between fungal stages of in vitro and in experimental models of infection. Exploitation includes the development infection. Furthermore, by identifying Candida genes necessary for these fungal stages of of novel fluorescent reporters for hypoxic infections and of novel targets for antifungals infection, we shall identify targets for novel therapeutic strategies to prevent or interfere combatting invasive infections. Results of the project will impact on therapeutic strategies with the transition from commensalism to pathological dissemination. by establishing antifungal sensitivities under various oxygen stress conditions and thereby help to optimize the treatment of invasive fungal disease. Publications related to the funded project:  Ernst JF, Tielker D (2009) Responses to hypoxia in fungal pathogens. Cell Microbiol. 11: 183-190.  de Dios CH, Roman E, Monge RA, Pla J (2010) The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence. Curr Protein Pept Sci 11, 693-703.  Horn F, Heinekamp T, Kniemeyer O, Pollmächer J, Valiante V, Brakhage AA (2012) Systems biology of fungal infection. Front Microbiol 3: 108. Stichternoth C, Fraund A., Setiadi S, Giasson L, Vecchiarelli A, Ernst JF (2011) Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans. Eukaryot Cell 10: 502-511.  Vödisch M, Scherlach K, Winkler R, Hertweck C, Braun HP, Roth M, Haas H, Werner ER, Brakhage AA, Kniemeyer O. (2011) Analysis of the Aspergillus fumigatus proteome reveals metabolic changes and the activation of the pseurotin A biosynthesis gene cluster in response to hypoxia. J Proteome Res 10: 2508-2524 |84 85 |

Project name: Characterisation of host cell pathways altered by effectors of Brucella, Project name: Impact of mobile genetic elements and horizontal gene transfer on bacteria- Chlamydia and Coxiella: identification of novel therapeutic targets (Acronym: CELLPATH) host adaptation: a genomics view (Acronym: MobileGenomics) Coordinator: Luís Jaime Mota, Instituto de Tecnologia Química e Biológica, Universidade Coordinator: Carmen Buchrieser, Institut Pasteur, Paris, France Nova de Lisboa, Lisbon,Portugal Partners: Philippe Glaser, Institut Pasteur, Paris, France Partners: João Paulo Gomes, National Institute of Health Dr. Ricardo Jorge, Portugal Ulrich Dobrindt, University of Münster, Germany Anja Lührmann, Universitätsklinikum Erlangen, Mikrobiologisches Institut, Germany Joachim Reidl, University Graz, Austria Carmen Plasencia, Applied Research using Omic Sciences [AROMICS], Spain Sören Schubert, Max von Pettenkoffer Institut, Germany Isabel Rodríguez-Escudero, Dpt. de Microbiologia II, Facultad de Farmacia, Universidad Tamara Smokvina, Danone, France Complutense de Madrid, Spain Abstract: Horizontal gene transfer (HGT) plays a major role in the diversification and the Suzana Salcedo, Centre d›Immunologie de Marseille-Luminy, INSERM, CNRS, Univ. de la evolution of bacterial species. Thus a comprehensive characterization and analysis of HGTs Mediterranee, France should allow to understand the emergence of specific e.g. disease related clones and the rapid Abstract: Brucella spp., Chlamydia trachomatis, and Coxiella burnetii are intracellular adaptation to changing environments like those encountered during the interaction with a bacterial pathogens causing human infections of clinical and public health relevance. As host either as a commensal, a probiotic or a pathogen and in the shift from a commensal to many other Gram-negative bacterial pathogens, they use specialised secretion systems a pathogen. MobileGenomics studies HGT and mobile genetic elements (MGE) in the human to manipulate eukaryotic host cells by injection of bacterial virulence proteins (effectors). gut environment and in the upper and lower respiratory tracts. Commensals, probiotics and However, current knowledge about how these pathogens establish infection is limited. important opportunistic bacterial pathogens are present in both niches. We are analyzing The overall purpose of this project is to characterize the function of effector proteins from Escherichia coli (pathogen, commensal, probiotic) Streptococcus agalactiae (commensal, Brucella, Chlamydia and Coxiella. Our specific objectives are to identify host cell signaling pathogen) Legionella pneumophila (human pathogen and environmental bacterium) and non- pathways targeted by effectors of Brucella, Chlamydia, and Coxiella; to characterize the typeable (commensal, pathogen) as niche-specific representatives molecular and cellular mode of action of effectors of Brucella, Chlamydia and Coxiella; Carmen of these three classes. We aim to increase the basic knowledge on genome variability, on the and to correlate the knowledge on the mode of action of the effectors to their sequence Buchrieser, mechanism leading to this variability and on the functional impact it has on host adaptation, variability and expression amongst different strains, including recent clinical isolates. The France colonization and virulence. The research is expected to improve our understanding on niche expected results may lead to the discovery of novel therapeutic approaches and could help "The status adaptation, colonization and virulence acquisition related to MGE and HGT, and to screen in the design of vaccines and novel diagnostics. In particular, the host signaling pathways seminars provide hints for more efficient probiotics and vaccines. enable the altered by one (or more) effector(s) will be excellent candidates as novel therapeutic targets. Publications related to the funded project: fruitful Furthermore, the knowledge that we will produce could also lead to the identification of  Gomez-Valero L, Rusniok C, Jarraud S, Vacherie B, Rouy Z, Barbe V, Medigue C, Etienne exchange of inhibitors targeting the effectors directly. new ideas. You J, Buchrieser C. (2011) Extensive recombination events and horizontal gene transfer have a chance shaped the Legionella pneumophila genomes. BMC Genomics 12:536 to present your work and get feedback and comments from scientists that are not necessarily in your field of research." |86 87 |

Project name: Helicobacter pylori diversity in pathogenesis, antibiotic resistance, and Project name: Analysis of the cellular mechanisms underlying the early response of the host to evasion from natural and vaccine-induced immune responses (Acronym: HELDIVPAT) stress induced by Listeria infection Acronym: LISTRESS Coordinator: Sebastian Suerbaum, Institute for Medical Microbiology and Hospital Coordinator: Trinad Chakraborty, Justus-Liebig University, Institute of Medical Microbiology, Epidemiology, Hannover Medical School, Hannover, Germany Giessen, Germany Partners: Ivo G. Boneca, Department of Microbiology, Institut Pasteur, Paris, France Partners: Pascale Cossart, Marc Lecuit, Institut Pasteur, Paris, France José Carlos Machado/Ceu Figueiredo, Institute of Molecular Pathology and Immunology, Lothar Jänsch, Uwe Kärst, Helmholtz Centre for Infection Research, Braunschweig, Germany University of Porto, Porto, Portugal Francisco García-del Portillo, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain Christine Josenhans, Institute for Medical Microbiology and Hospital Epidemiology, Didier Cabanes, Institute for Molecular and Cell Biology (IBMC), Porto, Portugal Hannover Medical School, Hannover, Germany Anat Herskovits, Yair Aharonowitz, Tel Aviv University, Dept. of Molecular Microbiology and Rainer Haas, Max von Pettenkofer-Institute, University of Munich, Munich, Germany Biotechnology, Ramat Aviv, Israel Peter Malfertheiner/Thomas Wex, Department of Gastroenterology, Hepatology and Abstract: The intracellular pathogen, Listeria monocytogenes breaches tissular barriers Infectious Diseases, Magdeburg, Germany to replicate within many cell types in the infected host. During cellular infection, microbial Abstract: Helicobacter pylori chronically infects more than one half of the world’s human presence is continuously monitored by intracellular pattern recognition receptors (PRRs) that population. The chronic gastritis that this infection always induces remains asymptomatic recognize evolutionary conserved structures (peptidoglycan, nucleic acids etc.,) and lead to in the majority of individuals, but can give rise to important complications, ranging from the induction of ubiquitous cytoplasmic quality and quantity control pathways such as the peptic ulcer disease to malignancies (gastric carcinoma, MALT lymphoma). Despite the fact ubiquitin-proteasome-system (UPS), endoplasmic reticulum stress (ER stress), and autophagy. that H. pylori is responsible for an estimated 590,000 cases of gastric cancer per year, Our studies have revealed that these processes are subverted by listerial factors at early time treatment remains difficult, with a rising rate of antibiotic resistance, and a vaccine is points following infection of the cell. Building on resources developed in the SPATELIS-project currently unavailable. Very high genetic diversity and variability are hallmarks of H. pylori. including mutant libraries for all cell wall-associated proteins, we analyse the role of the The HELDIVPAT project will build on the results of HELDIVNET (1st call) to address important Listeria factors that induce post-translational modifications and organelle remodelling to questions with direct relevance to treatment and prevention of H. pylori by antibiotics and overcome ER stress and autophagy. By combining functional genomic strategies to examine vaccines, respectively. A new consortium has been assembled to address these clinically bacterial and host factors we wish to identify interactions between listerial effector ligands relevant questions. In a closely networked approach, we will address the question how and host proteins in these processes. In addition, clinical material deriving from patients the genetic diversity/variability of H. pylori is connected to a) pathogenesis, b) its ability with inflammatory bowel disease harbouring mutations in predisposition loci will be used to evade immune responses raised during natural infections as well as those induced by to examine the contribution of these processes to limiting bacterial replication in a clinical currently available vaccines, c) resistance against antibiotics. To reach this ambitious goal, setting. Augmentation of protective host cell pathways represents a novel therapeutic option the consortium partners not only have a highly complementary set of technologies and to efficiently eliminate the invading pathogen. expertise at their disposal, but also have access to unique resources, including a previously Publications related to the funded project: uncharacterized strain collection from a human volunteer challenge study performed with  Pillich H, Loose M, Zimmer KP, Chakraborty T. Activation of the unfolded protein response a cagPAI carrying strain of H. pylori in the context of a vaccine trial, as well as one the by Listeria monocytogenes. Cell Microbiol 14:949-64, 2012. largest available globally representative collection of MLST-characterized H. pylori strains,  Seifart Gomes C, Izar B, Pazan F, Mohamed W, Mraheil MA, Mukherjee K, Billion A, including 30 strains whose complete cagPAI sequences are available. Aharonowitz Y, Chakraborty T, Hain T. Universal stress proteins are important for oxidative and acid stress resistance and growth of Listeria monocytogenes EGD-e in vitro and in vivo. PLoS One 6:e24965, 2011.  García-del Portillo, F., Calvo, E., D’Orazio, V., Pucciarelli, M.G. Association of ActA to peptidoglycan revealed by cell wall proteomics of intracelular Listeria monocytogenes. Journal of Biological Chemistry 286:34675-34689, 2011.  Camejo A, Carvalho F, Reis O, Leitão E, Sousa S, Cabanes D. The arsenal of virulence factors deployed by Listeria monocytogenes to promote its cell infection cycle. Virulence 2:379-94, 2011.  Iphöfer A, Kummer A, Nimtz M, Ritter A, Arnold T, Frank R, Kessler BM, Jänsch L, Franke R. Activity-based Ubiquitin Isopeptide Probes for Profiling Ubiquitin Linkage Specificity of Deubiquitinating Enzymes (Angew Chem, revised manuscript prepared). Patents related to the funded project 1. Iphöfer A, Franke R, Ritter A, Arnold T, Jänsch L. Novel Ubiquitin-Isopeptide Probes (pending) |88 89 |

List of the ERA-NET PathoGenoMics status seminars: Cologne , Germany, (2007) - First call kick-off of the funded projects The first trans-national call for projects was issued in 2006, resulting in 44 project applications, including 216 participating scientists. Twelve consortia were chosen for funding. The research teams focused on specific groups of bacterial and fungal genera, using the latest genomics tools and a variety of different approaches. Thanks to the huge quantity of genome sequences previously decoded, scientists were able to concentrate in particular on the complex network of protein interactions, screening them for signaling pathways relevant to disease, with the long-term aim of finding new Support for Young Researchers approaches for diagnostic,preventive and therapeutic strategies.

ERA-NET PathoGenoMics placed importance on promoting young scientific talent in the field of pathogenomics. The programme initiated measures to support the early independence of promising young scientists. In both the second and third JTCs, a module of the available funding was dedicated specifically to consortia of young scientists. The project leaders of these consortia had to be “young scientists", defined as researchers who had received the PhD or equivalent title within 2-9 years prior to the pre-proposal submission deadline. In the third JTC, a consortium of five young scientists from four countries, which incorporated basic, clinical and industrial perspectives, was funded.

Monitoring of the funded projects

Monitoring of the funded projects was conducted through annual scientific and financial reports prepared by the consortia and submitted to the Call Secretariat and to the CSC members. In addition, annual status seminars were organized, where project coordinators were invited to make oral presentations summarizing their findings to the audience, which included, inter alia, the CSC members representing the funding bodies and the core SAB, Paris, France (2008) - First call status seminar composed of 3-5 representatives of the application review panel. On the 7-8th April 2008 the first status seminar was held at the Institut Pasteur in In each of the annual status seminars, the coordinator of each funded project presented Paris. All twelve project coordinators attended and gave presentations summarising the consortium's findings to the funding agencies and scientific experts. In addition to the progress of their project during the first year. interim meetings involving only the project coordinators, two comprehensive symposia Villa Vigoni, (Italy (2009) First call status seminar and second call kick-off were organized in Tenerife, Spain, in January 2010 and January 2012, in which the final This seminar was held in conjunction with the Network of Excellence (NoE) reports of the first and second JTCs were presented. Most of principal investigators of the Europathogenomics. It served as the second status seminar for projects funded funded projects and many of the post-docs involved in the projects participated in these under the first call and as the kick-off seminar for the second call, which provided symposia. €16.3 million for 13 projects in applied pathogenomics. The annual written reports required from all funded project consortia provide additional Tenerife, Spain (2010) -First call final report and second call status seminar evidence of project success. More than 130 researchers from all around Europe gathered on January 18-19, 2010 The analysis of the reports also revealed that a number of bilateral and multilateral student in Tenerife for this seminar. The final report of the first call was presented at the exchanges took place between the partners of the consortia. These included meetings conference and all twenty five first and second-call projects were reviewed by the during conferences, workshops, seminars or short visits, which promoted discussions SAB as well as scientist involved in other projects. The seminar was also attended on strategies, problems encountered and progress related to the projects. An exchange by Dr. Matthias Stein-Gerlach, head of the Technology Transfer Department of the of researchers between laboratories also occurred to facilitate technical training and the Lifesciences Section of Max-Planck- Innovation Gmbh. conduct of experiments. Vienna, Austria (2011) -Second call status seminar and third call kick-off Held in Vienna March 2011, this status seminar served as the venue for the launch of the third call research projects. Nine new projects focusing on translational |90 91 |

pathogenomics were presented and progress reports were presented for the 13 second-call projects. In addition, a discussion on future scientific trends in the field of pathogenomics was held. The transition to post-genomic research employing data in the field of pathogenomics, we need the closest possible cooperation in systems biology and synthetic biology approaches was discussed. The forum also Europe to bring together the best heads and to avoid the needless repetition of addressed the issue of globalization and the implications of growing migration on research in different countries.” the spread of infectious disease. Other subjects included infectious diseases in aging The first transnational call for projects, issued last year, was well received: a populations and host-pathogen interactions. total of 44 project applications were submitted, including 216 participating Tenerife, Spain (2012) - Second call final report, third call status seminar scientists. A jury has finally chosen twelve consortia for funding and these are On January 23-24, 2012 the final ERA-NET PathoGenoMics status seminar on the now beginning their work. “By the year 2010, we will be allocating a total sum of projects funded by the second and third joint calls took place, once again, in Tenerife. around 14 million Euro, which will be provided by the respective national funding The final report of the second call was presented and the research launched under agencies of the research groups participating “, said Prof. Frank Laplace from the the third call was brought up for its first review. German Federal Ministry of Education and Research. Many of the research teams are focusing on specific groups of microorganisms, including the bacterial genera Helicobacter, Escherichia, Listeria, Streptococcus and Chlamydia and the fungal genera Candida and Pneumocystis. The diseases caused by these microorganisms are as varied as the microorganisms themselves but the key question is often the same: why do largely harmless bacteria or fungi mutate into dangerous, disease-causing agents? To get to the PRESS RELEASE: bottom of this and other mysteries, the researcher groups are using the latest SHEDDING LIGHT ON MICROORGANISMS THAT CAUSE DISEASE genomics tools and a variety of different approaches. One aim is to shed some TWELVE EUROPEAN CONSORTIA BEGIN WORK UNDER THE UMBRELLA OF THE ERA- light on the microorganisms themselves. Thanks to the huge quantity of genome NET PATHOGENOMICS sequences that have previously been decoded, scientists will concentrate in For human beings, microorganisms play a crucial part in a number of respects: particular on the complex network of protein interactions, screening them for they can be both useful inhabitants of the body and dangerous pathogens. signalling pathways relevant to disease. In addition, the researchers are looking This dual role has long made them a fascinating branch of scientific research. at the respective host cells, again with the hope of identifying the factors that Particularly on a genetic level, disease-causing microorganisms are increasingly play an essential part in the development of disease. Based on their results, the being analysed in the hope of identifying critical factors that might be scientists’ long-term aim is to find new approaches for diagnostic, preventive therapeutically applicable. This will also be the aim of twelve European research and therapeutic strategies. consortia within the ERA-NET PathoGenoMics network, which have recently started their work. The ERA-NET PathoGenoMics network was initiated in 2004 and is one of around 80 ERA-NET networks aimed at counteracting the fragmentation of the European Research Area. The ERA-NET scheme is a funding instrument of the European Commission, first introduced in the Sixth Framework Programme. The underlying intention is to step up the cooperation associated with research activities carried out at a national or regional level in the member states. The ERA-NET PathoGenoMics was initiated by a group of research ministries and funding agencies from ten different countries to promote genomic research on pathogenic microorganisms (pathogenomics) in Europe. In the meantime, 15 partners from Austria, Finland, France, Germany, Hungary, Israel, Latvia, Portugal, Slovenia and Spain are cooperating under this single umbrella. As Julio Barbas from the Spanish Ministry of Research says, “In view of the multitude of |92 93 |

ERA-NET PathoGenoMics October 2009 WP 9: Science to Society ERA-NET PathoGenoMics May 2009 WP Leader: Israel, Chief Scientist Office, Ministry of Health (CSO-MOH) NEWSLETTER 5 NEWSLETTER 6 The objective of the "Science to Society" activities was to build bridges between the ERA-NET PathoGenoMics ANNOUNCEMENT: Hungary research community and society at large, particularly regarding information exchange. It Hungary JOINT STATUS SEMINAR 2010 OF ERA-NET PATHOGENOMICS. January 18-19, 2010, Tenerife, Canary Islands, Spain Finland set out to emphasize the benefit of collaboration in the field of pathogenomics research Finland

ERA-NET PathoGenoMics organizes a Status Seminar on the projects funded under the frame of its Spain Spain and to increase public awareness of the importance of this research. This work package first and second Joint Calls. It will take place at H10 Costa Adeje Palace Hotel, on the southern coast of Tenerife on January 18-19, 2010.

ERA-NET PathoGenoMics status seminar, Villa Vigoni, Loveno do Menaggio, Lake Como, All project coordinators and partners of the research projects funded through the two calls emphasized the role of the public, not only as the ultimate beneficiary of the research, but Italy, 12-14.5.09. More information will follow in our next newsletter. ERA-NET PathoGenoMics areMarch invited to present 2010 their projects at the status seminar. In addition, we inviteERA-NET one junior PathoGenoMics Jan 2011 Germany Germany researcher per partner from each project of the first call to present his/her findings as a poster.

As part of ERA-NET PathoGenoMics' innovation work package, Presenters of lectures and posters have to submit an abstract of their presentation/poster not Israel as a source of influence on decision-makers in the formation of public policy. To achieve a strategy paper on pathogenomics, innovation and public health Israel later than December 11, 2009. was composed. A brief executive summary follows. NEWSLETTER 7 NEWSLETTER 8 For the whole document and more details on ERA-NET PathoGenoMics, France this goal, the work package leaders consulted with experts in public relations and science France The PathoGenoMics PhD Award is an initiative please see: www.pathogenomics-era.net PathoGenoMics of the ERA-NET PathoGenoMics partner countries to recognize three outstanding PhD

The field of anti-infective drugs is facing a crisis FEMS, NoE EuroPathoGenomics and Hungary PhD Award 2011 communications from academia and science museums. Despite the ever growing need for new theses in the PathoGenoMics field (Genome Austria due to three major factors: antimicrobial agents, a number of factors make Information | Application: Austria based research on human-pathogenic bacteria

Hungary ERA-NET PathoGenoMics Conference (a) pathogens are constantly developing their development economically unattractive. www.pathogenomics-era.net and fungi) completed during 2010. resistance to existing drugs (especially at the First, health authorities agree on the need to Deadline for Proposal Submission:

Detailed information on the seminar and the registration: Finland The dissemination of information to the public was conducted via a regularly updated hospital setting); (b) the development of new limit the use of broad spectrum antimicrobials in www.pathogenomics-era.net/index.php?index=332 28th Febuary 2011 Award Endowment: 2000€ antibacterial agents is nearing a standstill order to minimize the selective pressure driving On projects funded in the first and the second calls: Finland Portugal (new antibacterial agents constitute merely 6 resistance. Portugal www.pathogenomics-era.net/Projects-Public Award presentation will take place during the 4th FEMS congress, Geneva, June 2011

of 506 drugs disclosed in the developmental Second, the products are almost certainly Spain Further information from: programs of the largest pharmaceutical short-lived, since resistance to the product website (http://www.pathogenomics-era.net) which published not only news items, such Soile Juuti, [email protected], Tel: +358 40 565 1529

and biotech companies in the U.S.); (c) a is likely to rise with time. ThirdSpain , aging of the Julio Barbas, [email protected], Tel: +34 9160 38 384 dearth of reliable diagnostic and monitoring Marion Karrasch, [email protected], Tel: +49 2461 6245

Slovenia Western population has shifted drug discovery Slovenia tools for infectious disease complicates efforts towards agents that treat chronic medical ERA-NET PathoGenoMics Germany as the JTCs, but also findings from other activities and work packages. treatment and diminishes its efficiency. conditions. Finally, newly developed agents chose 9 projects to be funded under the frame of the Germany Latvia Latvia third multinational joint call. The three-year funding is Israel A 'Science to Society' workshop was held with all ERA-NET partners and experts from ERA-NET PathoGenoMics Newsletter No.5 | May 2009s ERA-NET PathoGenoMics Newsletter No.6expected | October 2009 sto begin in March 2011 Israel Scientific committee: A glimpse at the projects… U. Dobrindt, J. Hacker, M. Karrasch, T. Korhonen, France B. Nagy, E. Oswald, E. Ron, BE. Uhlin the field of science communications in Vienna, January 2007. After taking into account Analysis of the cellular mechanisms underlying the early response of the Organizing committee: France G. Blum-Oehler, A. Demuth, L. Emody, M. Kerényi, host to stress induced by Listeria infection / LISTRESS (Listeria-induced G. Schneider, Z. Tigyi, I. Tóth cellular stress during infection) Austria the various target groups ERA-NET addresses, the workshop articulated the following Scientific information: Project Coordinator: Trinad Chakraborty / Torsten Hain Dr. Levente Emody University of Pécs, Medical School, [email protected]

Austria Pécs, Hungary, Department of Medical Microbiology and Immunology H – 7624 Pécs, Szigeti út 12. April 22-24, 2010 Project partners: Pascale Cossart FR, Marc Lecuit FR, Jürgen Wehland, Lothar Jänsch DE, Tel.: +36 72 536 001 ext. 1904 Fax: +36 72 536 253 Francisco García-del Portillo ES, Didier Cabanes PT, Yair Aharonowitz, Anat A. Herskovits IL

programmatic objectives: Portugal E-mail: [email protected] Conference venue: Hotel Palatinus Pécs: Cultural Capital of Europe, 2010 ERA-NET PathoGenoMics June 2011 Congress organizer: ERA-NET PathoGenoMics June 2011 This project aims to analyse the roleERA-NET of the Listeria patientsPathoGenoMics with inflammatory bowel Aprildisease - har 2012 Portugal Registration, Travel and Accomodation factors that induce post-translational modifica- bouring mutations in predisposition loci. Interact- Tensi Congress – Pécs TENSI Aviation Kft.  create and maintain an expert Q&A forum for the first three years of the ERA-NET tions and organelle remodelling in order to over- ing targets and downstream events leading to the H – 7621 Pécs, Teréz u. 17.

Tel.: +36 72 513 993 Fax.: +36 72 514 094 Slovenia come host recognition and response. Bacterial induction of cell autonomous defences and innate E-mail: [email protected] ligands as well as their intracellular pattern rec- immune signalling pathways will also be pursued, Web: www.tensi-congress.hu NEWSLETTER Slovenia 9 NEWSLETTER 9 ognition receptors (PRRs) will beNEWS identified using and interactions betweenLETTER Listeria effector ligands 10 programme; www.tensipecs.hu functional genomic strategies, 3D- and 2-photon and host proteins will be mapped. Latvia imaging technologies, and clinical material from Latvia

 construct an interactive modular teaching aid in English targeted at junior high school ERA-NET PathoGenoMics Newsletter No.7 | March 2010s

Hungary Hungary ERA-NET PathoGenoMics Newsletter No.8 | Jan 2011s students and the general public (http://www.ict-science-to-society.org/Pathogenomics/ Finland Finland index.aspx); Spain Spain

 produce and distribute a series of newsletters to the scientific community highlighting On March 28-30, 2011 ERA-NET PathoGenoMics held its 2nd joint call status seminar and 3rd joint call kick-off meeting in Vienna. After two interesting days ERA-NET PathoGenoMics Germany Germany of scientific presentations, the partners of the various funding organizations ERA-NET PathoGenoMics is a consortium of 13 funding organizations from brainstormed in preparation for the sequel program, named ERA-INFECT, 9 countries (Austria, Finland, France, Germany, Hungary, Israel, Slovenia, events or major ERA-NET activities, such as the PhD Award ceremonies and status Israel ERA-NET PathoGenoMics Israel planned for the funding period of 2012-2015. Spain, and Portugal) which, among many other activities, implemented 3 2012 Joint Status Seminar transnational joint calls, through which more than 41M € of national funding seminars of the funded projects. The newsletters were included in the PathoGenoMics ERA-NET PathoGenoMics, focusing on transnational ERA-INFECT. As part of this effort, during the status January 23-24, 2012, Tenerife, Canary Islands, Spain have been provided to support transnational research projects in the field of France research in genomics of human pathogens seminar and the NSC/EB meeting held in Vienna (March France microorganisms, is a consortium of 13 funding 2011), a discussion was propped up with the genome research on pathogenic microorganisms. organizations from 9 countries. The program has been participating scientists on the future scientific trends in ERA-NET PathoGenoMics is organizing a Status Important dates: website and distributed to the scientific community and to decision makers by the very successful in publishing and handling 3 joint calls. the field of pathogenomics. Interesting suggestions The first joint call for research proposals was The status seminar consisted of lectures and poster nd rd Hotel room booking (highly recommended) While the 1st call focused on basic research, the 2nd & included progressing into post-genomics research in the Seminar on the projects funded under its 2 and 3

Austria Austria launched in 2006, and was followed by two presentations of the research results. The participants r d joint calls, which will take place at the H10 Costa by October 1,2011 3 calls took a more applicable approach and included field of systems biology and synthetic biology; tackling additional joint calls launched in 2008 and 2010. were able to get an overall picture of the research Adeje Palace Hotel, on the southern coast of Deadline for registration also companies and clinicians. The total funding of all 3 the issue of globalization and diseases that are promoted While the first call focused on basic research, the undertaken under the framework of the ERA-NET Tenerife, on January 23-24, 2012. October 30,2011 partners. In total eleven such newsletters were disseminated. See (http://www. calls reached almost 43 Million Euro. by migration; the issue of infectious diseases in aging second and third calls extended to applicable PathoGenoMics and, at the same time, could The transnational calls were complimented with populations; and host-pathogen interactions. All these and Deadline for abstract submission All the coordinators and partners of the research research in the prevention, diagnosis, treatment and strengthen existing research collaborations and additional activities, such as the PathoGenoMics Ph.D. more are currently being considered and evaluated. December 14, 2011 Portugal projects funded through the two calls are invited to Portugal monitoring of infectious diseases. hopefully create new ones. award, to support young scientists, the creation of a In closing, we wish to share with you some thoughts present their projects. In addition, one junior pathogenomics-era.net/News); comprehensive website publishing brochures, Throughout the years of ERA-NET PathoGenoMics The following interviews describe three of two members of the PathoGenoMics steering researcher per partner from each project of the first Seminar organizers: newsletters and press releases. Following this fruitful funding activities, annual status seminars were research projects presented at the 2012 status committee: Dr. Julio Barbas, Staff Scientist at the call is invited to present his/her findings as a poster. transnational research framework, all partners wish to organized in which scientists from each funded seminar. These are only examples of the exciting, National Research Council in collaboration with the Dr. Julio Barbas / [email protected]

Slovenia continue the ERA-NET PathoGenoMics (2004-2012) Slovenia project presented their results. diverse and leading research supported under the Ministry of Science and Innovation, Spain, one of the A preliminary agenda, hotel room prices and contact Ms. Jess Jackson / [email protected]  produce informative thematic flyers to the public; collaboration with a widened scope and partnership into information of the hotel are available at: ERA-NET PathoGenoMics collaborative transnational leading active partners of ERA-NET PathoGenoMics, Ministry of Science and Innovation, Spain On January 23-24, 2012 the final ERA-NET a second funding phase – ERA-INFECT. umbrella, which, we believe, could not have been and Dr. Bülent Genç from Forschungszentrum Jülich www.pathogenomics-era.net PathoGenoMics status seminar on the projects Dr. Bülent Genç / [email protected] achieved otherwise. funded by the 2nd and 3rd joint calls took place, Latvia The funding partners are now in the process of defining GmbH (FZJ), Germany, the Coordinator of ERA-NET Latvia We are looking forward to a successful seminar! ERA-NET PathoGenoMics Coordinator  the specific research areas which will be the focus of PathoGenoMics. once again, in the beautiful island of Tenerife in the publicize the "Science to Society" and "Communications" awards to researchers that were Canary Islands, Spain. active in communicating scientific knowledge to the public; ERA-NET PathoGenoMics Newsletter No.9 | June 2011s ERA-NET PathoGenoMics Newsletter No.9 | June 2011s Produced by CSO-MOH, ISRAEL ERA-NET PathoGenoMics Newsletter No.10 | April 2012  present ERA-NET activities and opportunities at scientific and policy-maker conferences (ERA-NET help desks);  publish press releases on various ERA-NET activities or achievements (http://www. pathogenomics-era.net/News). In total 19 press releases were published over the duration of the PathoGenoMics programme;  produce interim and final brochures on ERA-NET achievements targeted at policy- makers;  disseminate printed and electronic materials through meetings, internal mailing lists, and business news services, such as "Business Wire". Further information on Science to Society activities is available at: http://www. pathogenomics-era.net/ScienceToSociety |94 95 |

WP 10: Consortium Management WP Leader: Germany, Federal Ministry of Education and Research (BMBF) and Project Management Juelich (PtJ) This work package dealt with the challenging task of coordinating a multinational organization, including the financial management and administration of ERA-NET and compliance with Commission reporting requirements. The ERA-NET activities were conducted under continuous collaboration with similar EU networks, such as the Network of Excellence (NoE) Europathogenomics and the Joint Programming Initiatives (JPI). Several mutual meetings were held, including the 2009 ERA- NET status seminar at Villa Vigoni Italy in May 2009 and the joint ERA-NET PathoGenoMics- Europathogenomics meeting in Pecs, Hungary in April 2010. Collaboration with the Federation of European Microbiology Societies (FEMS) engendered the annual ERA-NET PathoGenoMics PhD award, which recognises promising research conducted by PhD students.

WP 11: Evaluation of ERA-NET PathoGenoMics Activities WP LEADER: Portugal, The Foundation for Science and Technology (FCT) WP 11 was added to the ERA-NET PathoGenoMics' Description of Work (DoW) in 2007. The primary objective of this work package was to evaluate the overall efficiency and effectiveness of ERA-NET PathoGenoMics activities and to lay the foundation for future development of transnational pathogenomics research. The work package comprised two major tasks:  Evaluation of ERA-NET PathoGenoMics activities;  Holding a workshop on the future course of the ERA-NET PathoGenoMics; On the basis of the outcomes of the evaluation performed in this work package, the participating organisations decided to extend their participation in a long-term cooperative European programme in the field. New partners were invited to join the proposed network, entitled Infect-ERA. The overall efficiency and effectiveness of the ERA-NET PathoGenoMics programme and its activities were evaluated by participating scientists and agencies to better prepare the next stage of transnational pathogenomics cooperation. The evaluation of the ERA-NET activities started during the fourth year of the project and continued up to the end of its activities. An extensive questionnaire was sent to all partners to gather feedback on PathoGenoMics' achievements and the prospect of future concerted action. The questionnaire was structured in three sections: a) general ERA-NET goal attainment; b) assessment of concepts and tools for transnational activities and the implementation of transnational research and training activities; and c) assessment of ancillary PathoGenoMics activities. The results of the survey showed that overall, the partners were very positive about the network. One of the recommendations for the future was that special attention be given to intellectual property rights, ideally, by including Example of the Business Wire dissemination list of the ERA-NET PathoGenoMics press experts in this area to assist the research consortia on an on-going basis. releases. Note the popular websites such as CBS news, Yahoo Finance, Biotechnology etc. A second questionnaire was developed and sent to the scientific community in The dissemination activities were followed by 1 and 24-hour reports and visits to monitor the participating countries. 98 responses were collected from researchers in the the actual impact of the press releases nine participating countries. The majority of the respondents were successful joint |96 97 |

transnational call applicants, primarily principal investigators. Nevertheless, a sizable in the follow-on Infect-ERA initiative. As a result of the SWOT/KIA analysis, improvements portion (25%) of the respondents, were researchers whose proposals were rejected. The were implemented in the Infect-ERA description of work (DoW), including the extension questionnaire was divided into seven sections: a) identification; b) evaluation of the ERA- of the External Advisory Board and the institution of better coordinated reporting NET PathoGenoMics three calls; c) call administration; d) a specific section dedicated solely procedures. Web-based social platforms for communication and dissemination such as to PathoGenoMics grant holders; e) evaluation of the programme's affect on international Twitter, Facebook, Linkedin, YouTube and Wikipedia will be used in Infect-ERA to facilitate collaboration; f) evaluation of the potential for future commercialization of research communication and partnering between the researchers involved in the Infect-ERA joint findings; g) general remarks. Overall, the scientists who participated in the survey found calls. The SWOT analysis also suggested promoting Infect-ERA through short video clips. PathoGenoMics to be a beneficial and well-managed programme. They pointed to several In conclusion, the positive experience of PathoGenoMics and its accomplishments served areas in which the programme yielded important added value: funding options, exposure as the foundation for the proposal of the follow-on ERA-NET, Infect-ERA. The Infect-ERA to new methodologies, exchange of information and know-how, initiation of new lines of proposal has been approved by the Commission and the first JTC under this programme is research, access to expertise not available in their country, infrastructure sharing, access scheduled for early 2013. to biological material, the establishment of new international networks, and on-going ERA-NET ERA-NET collaboration with consortium colleagues. Furthermore, participation in PathoGenoMics PathoGenoMics PathoGenoMics projects was also perceived as a excellent gateway for participation in other international RESEARCH SUBJECTS CONSORTIA COMPOSITION

The ERA-NET PathoGenoMics funds research on genomics of human pathogens, f o c u s i n g on B a c t e r i a and Fungi. 1. The number of participating countries per 4. 17 out of 34 consortia included clinicians Bacteria Fungi collaborative activities. Forty out of the 98 researchers who participated in the survey stated consortium ranged f r o m 3 t o 7. ERA-PathoGenoMics implemented the d i r e c t interaction of Table 1 – Participating countries per consortium interdisciplinary groups, including clinicians. 17 out of 34 consortia 26% established partnerships with clinicians (Fig. 3). Some of these Call Consortium acronym AU BE DE DK ES FI FR HU IL PT SI SE UK USA F r o m the p r o j e c t s funded 74 % w e r e HELDIVNET DE FI FR PT interactions we re done through the establishment of connections with Pneumocystis ES FR USA hospitals that did not belong to the consortia. Pathogenomics 74% FunPath AU DE ES FR that had already embarked on various types of new collaborative activities, such as: EPS-MATRIX ES FR UK GLYCOSHIELD DE ES FR 7 1 FaecalVir DE ES FR PT proposals on bacteria research. 6 KinCan DE FR IL 5 ECIBUG AU DE FI FR P a t h o S t r e p DE FR IL 4 X DE FI FR HU IL SE 3 RNAi-Net AU DE ES FI FR IL PT 2

SPATELIS DE ES FR IL PT partners clinical  the establishment of additional collaboration with consortium colleagues (at times CoMeVac BE DE FI FR 1

Helicobacter with Numberof consortia BACTERIA FUNGI FunGen DE ES FR 0 Salmonella UTI-Interference DE FI HU IL SE 1st Call 2nd Call 3rd Call ADHRES DK ES FR PT Pseudomonas sncRNAomics DE FR SI 2% 2% Fig. 3 - Number of consortia integrating clinical partners. Staphylococcus TRANSPAT AU DE ES FR 2% 2% 10% 5% 8% 8% 2 ANTIFUN DE ES FR 7% Enterococcus Pneumocystis CDIFFGEN AU DE FR PT SI 2% Chlamydia ChlamyTrans AU DE FI HU 7% extended to other topics); Candida Streptomics AU FI FR 5% Streptococcus PATHOMICS AU DE ES FR 5. 18 (out of 34) consortia included partners f r o m 5% 10% Escherichia 34% METAGUT AU DE ES PT industry Listeria Cryptococcus COLIEVOL AU DE ES FR 42% LISTRESS DE ES FR IL PT 7% Neisseria aspBIOmics AU DE ES FR 5% Aspergillus Among the 34 PathoGenoMics funded p r o j e c t s , 18 consortia included Mycobacterium O X Y s t r e s s AU DE ES 10% HELDIVPAT DE FR PT partners f r o m industry (Fig.4). A t o t a l number of 21 co m p a n i e s 12% Legionella 3 MobileGenomics AU DE FR 7% 8% Fusarium integrated the 18 funded consortia of the t h r e e ca l l s (Fig.5 and t a b l e 2).  the initiation of cross-project collaboration at the annual PathoGenoMics meetings; Klebsiella ARMSA ES FR PT CELLPATH DE ES FR PT The industry participation r a n g e d f r o m 1 to 3 companies per consortium. Burkholderia GeMoA DE ES FR Clostridium CANDICOL AU DE FR HU 12 14

Brucella The coordinator country of the consortium is indicated in bold and blue. Proportion of bacteria genera studied. Proportion of fungi genera studied. 10 12 Coxiella 10 8 8 6  applications to other international grants with consortium partners and others e.g. 7th 6 4 2. The majority of the consortia was composed by 4 2 2

Table 1- Consortia titles on b a c t e r i a r e s e a r c h Table 2 - Consortia titles on fungi r e s e a r c h participation industry researchers f r o m 3 or 4 countries. Numberof companies Number of consortia with Numberof consortia 0 0 • Parasite and host genetic diversity in Helicobacter infections. • Pneumocystis Pathogenomics: unravelling the Colonization-t o -Disease shift. 1st Call 2nd Call 3rd Call 1st Call 2nd Call 3rd Call • Exploring Protein Secretion within the bacterial biofilm m a t r i x . • Large scale screening of potential key factors involved in the commensalism / virulence transition of Fig. 4 - Number of consortia with industrial Fig. 5 - Number of participating companies. • Genomic Approaches to Unravel the Molecular Mechanisms of Pathogenicity in the Human Fungal Enterococcus faecalis. partners. Framework Programme projects, other ERA-NET projects, EU-projects, ECDC projects; Pathogen Candida glabrata. • European Initiative to Fight Chlamydial Infections by Unbiased Genomics. • A comparative molecular analysis of GAS and GBS pathogenesis. T w o co n s o r t i a f r o m the f i r s t ca l l also established interactions with • S u r f a c e Modulation of the Fungal & Host Response using a Genomic Approach. • Deciphering the intersection of commensal and extraintestinal pathogenic E. coli. companies that did not directly integrate the p r o j e c t . • A global RNAi approach to unravel eukaryotic host functions that modulate bacterial infections. • Systematic analyses of kinase and phosphatase function in morphological, environmental, and • S p a t i o -t e m p o r a l analysis of Listeria-host protein interactions. virulence responses of the human fungal pathogen Candida albicans. • Genome wide screening of the human pathogen Neisseria meningitidis for proteins enhancing serum Table 2– Participating companies in the consortia.  resistance and evaluation of their vaccine p o t e n t i a l . Fig. 1 - Proportion of the PathoGenoMics consortia with 3, 4, 5, 6 or 7 countries. Call C o m p a n y Country bilateral collaboration with researchers from non-EU countries, such as the United States • Transcriptional networks controlling virulence in filamentous fungal pathogens. • Functional genomics of host-pathogen interactions using high-throughput screenings: a novel 1 Gesellschaft für Biotechnologische Forschung GmbH Germany approach towards identifying therapeutic/prophylactic t a r g e t s . • The cell wall as a target to improve antifungal therapy against Aspergillosis. Bio-Iliberis R&D Spain • Pathogenomic approach to explore the use of bacterial interference as alternative treatment of BioAlliance Pharma F r a n c e recurrent urinary tract infections. • I n v a s i v e aspergillosis: Biomarkers for prevention, diagnosis and treatment response . Procomcure GmbH Austria • ADHRES-S i g n a t u r e Project. 3. The majority of the consortia involved 6 partners medac GmbH Germany • High throughput comparative sncRNAome analysis in major Gram-positive human pathogenic bacteria: • Human fungal pathogens under oxygen stress: adaptive mechanisms to hypoxia and reactive oxygen functional characterization by a systems biology approach and peptide nucleic acid drug design. species and their consequences for host interaction and t h e r a p y . Within the t h r e e ca l l s , the consortia c o n s i s t e d of r e s e a r c h teams f r o m 3 Bacterial Vaccine Program, GlaxoSmithKline Biologicals SA Belgium and Canada; RNAx GmbH Germany • Pathogenomic of increased Clostridium difficile virulence. to 16 laboratories. The majority of the consortia (47%) involved 6 • Transcriptome-based Monitoring and Eradication of Chronic Chlamydial Infection. • Understanding colonisation and the transition to pathogenic dissemination by Candida species: Life Sequencing S.A. Spain partners (Fig. 2). 2 • Mechanisms and modulation of innate immune responses to Streptococcus pneumoniae and S. towards early diagnostic and therapeutic approaches. Anagnostics Bioanalysis GmbH Austria pyogenes. L i f e w i z z Lda P o r t u g a l • H o s t -pathogen protein-protein interactomes and their influence on the host metabolome. Merck, Sharp & Dohme de España, S.A. Spain • Development, prevention and early diagnostic detection of Clostridium difficile-associated F e b i t Biomed GmbH Germany pseudomembranous colitis - an interdisciplinary n e t w o r k . Candida albicans Escherichia coli Genedata Bioinformatik GmbH Germany  joint Ph.D. thesis supervision. • Identification of hot spots of divergence and rapidly changing genes within Shiga toxin-producing Escherichia coli. I n t e r c e l l AG Austria • Analysis of the cellular mechanisms underlying the early response of the host to stress induced by B a y e r CropScience SA F r a n c e Listeria infection. bioMérieux F r a n c e • Helicobacter pylori diversity in pathogenesis, antibiotic resistance, and evasion from natural and LabDia LabordiagnostikGmbH Austria v a c c i n e -induced immune responses. Applied Research using Omic Sciences S.L. (AROMICS) Spain 3 • Impact of mobile genetic elements and horizontal gene transfer on bacteria-host adaptation: a GlaxoSmithKline T r e s Cantos Medicnes Development Centre (GSK TCMDC) Spain genomic v i e w . Collaboration was also fostered among researchers that did not receive PathoGenoMics Fig. 2 - Proportion of the PathoGenoMics consortia with 3, 4, 5, 6, 7, 8, 9 or m o r e than 10 Danone R e s e a r c h F r a n c e • Global analysis of antisense regulatory mechanisms in Staphylococcus aureus. r e s e a r c h partners. E v o c a t a l GmbH, Düsseldorf Germany • Characterisation of host cell pathways altered by effectors of Brucella, Chlamydia, and Coxiella: identification of novel therapeutic t a r g e t s . • A genome-wide approach for characterizing the mode of action of novel compounds against funding; however, these usually did not extend beyond the application to subsequent tuberculosis. PathoGenoMics calls. Hence, the creation of a framework for transnational finance established in the ERA-NET initiative has apparently become a critical factor in generating and sustaining long-term collaborative activities. ERA-NET ERA-NET PathoGenoMics PathoGenoMics In summary, the responses to both questionnaires favour the continuation of joint GENERAL OUTPUT OUTPUT: TOP LEVEL PUBLICATIONS

transnational calls. Respondents suggested that the evaluation process and the feedback 1. 5% of the consortia papers we re published in 2. Bilateral and multilateral interactions within the journals with impact f a c t o r above 20. financed consortia

F ro m the 25 consortia of the f i r s t and s e co n d ca l l s , 11 co n s o r t i a (out of Several bilateral and multilateral interactions took place between the to scientists could be improved and that the mobility of human resources and the 12) f r o m the f i r s t ca l l and 6 (out of 13) f r o m the s e co n d call generated a partners of the consortia. These included meetings during conferences, t o t a l of 74 peer-reviewed j o i n t publications between the consortia workshops, s e m i n a r s or short visits, which promoted discussions on partners (T a b l e 1). strategies, problems encountered and p r o g r e s s related to the p r o j e c t s . The quality of the articles was elevated, given that 42% of them (31 Exchange of researchers also o c c u r e d between laboratories to facilitate articles) w e r e published in journals with an impact f a c t o r (IF) above 5 technical training and the performing of experiments. (Fig.1). Of note, 2 p a p e r s we re published in Science (IF = 29.747), 1 in development of young scientist should be further encouraged and reinforced. N a t u r e (34.480) and 1 in N a t u r e Medicine (IF = 27.136). No articles we re Table 2 – Quantification of the interactions e x i s t i n g between the consortia m e m b e r s . published in journals with IF between 10 and 20. Project discussions Training/Performing experiments

Meetings between Meetings between S t a f f exchange between 2 partners ≥ 3partners laboratories Table 1 1 cal l 9 22 37 Number of articles 2 cal l 23 32 34

The assessment of the ERA-NET PathoGenoMics activities was summarized in a SWOT 1 Call 2 Call T o t a l T o t a l 32 54 71

63 11 74 3. Three websites were created

The consortia FunPath, TRANSPAT and CDIFFGEN developed websites. /KIA (Strengths, Weaknesses, Opportunities, Threats / Keep, Improve, Add) analysis P a r t of the websites is public and part is restricted to the p r o j e c t partners. conducted at the “The Future of PathoGenoMics” workshop held in Lisbon in July 2011. The http://funpath.cdl.univie.ac.at/ Fig. 1 - Distribution of the published papers according to the IF. http://bioinfo.cipf.es/starazona/transpat/doku.php http://www.cdiffgen.com/ The majority of the papers (81%) involved the cooperation of two Fig. 3 – Websites created by some consortia. partners of the consortia (Fig. 2). However, these papers came often f ro m different p a r t n e r s within the consortia, occuring interactions between workshop was attended by the partners, potential future partners, the External Advisory a l m o s t all the members of the p r o j e c t . Only one j o i n t publication involved all the consortium members (7 partners). 4. 18 researchers from PathoGenoMics countries received the PhD a w a r d

ERA-NET PathoGenoMics has been recognising outstanding PhD theses in 60 the field of pathogenomics r e s e a r c h . The network r e c o g n i s e t h r e e Board members and other invited scientists, intellectual property rights experts and 50 researchers per y e a r. Since 2006, 18 researchers f r o m 6 different 40 nationalities we re a w a r d e d ( t a b l e 3) 30 Table 3 20 Country Number of Awards 10 F r a n c e 5 Number of published papers Numberof published 0 2 partners 3 partners ≥ 3 partners Germany 3 technology transfer specialists. Number of partners per consortium I s r a e l 2 P o r t u g a l 3 Fig. 2 – Number of partners per consortium involved in the joint publications. Slovenia 2 The workshop participants discussed the findings of the programme's evaluation and Spain 3 STRENGTHS: WEAK POINTS:

The d a t a presented constitute an evidence of a true cooperation Despite the cooperation between the partners, some consortia did not between the consortia partners: d i r e c t interaction between g e n e r a t e a n y publication, particularly those f ro m the s e co n d ca l l . This expressed their willingness to participate in a future ERA-NET programme on human interdisciplinary groups, including industry and clinicians; bilateral and co u l d be only related with the time r e q u i r e d to the publication p r o c e s s . multilateral mobility between the laboratories involved; elevated Some of the papers are in the submission s t a g e and should be published number of j o i n t publications in journals with high impact f a c t o r . soon. M o re o ve r, only one article with the involvement of all the p a r t n e r s was generated. infectious microorganisms. Strengths of the ERA-NET PathoGenoMics programme, such as the JTC procedures, the Call Secretariat, the partnering workshops and status seminars, the support of young researchers, communication activities (newsletters and press releases) and project monitoring, were designated as features that should be kept Posters presented at the Lisbon workshop, July 2011 |98 99 |

INTERVIEW Dr. JULIO BARBAS Staff Scientist at the National Research Council in Collaboration with the Ministry of Science and Innovation, Spain

What were some of the challenges that ERA-NET PathoGenoMics had to deal with at the beginning? Launching the first call was a big challenge. For most of the partners this was their first experience working within the ERA-NET framework. We had to hold more than five meetings in preparation for the first call, and every word was discussed extensively. Each country wanted to promote its own national ideas. But we finally succeeded and have been using the procedure that was formed in 2005 as the basis for What is the Joint Programming Initiative (JPI)? other ERA-NET consortia. For example, we used the PathoGenoMics The concept of Joint Programming Initiative (JPI) was launched first call wording and agenda as a reference for ERA-NET Neuron, by the European Commission in 2008 with the aim of increasing which published a call in 2007, and for ERASysBio, in 2009. This was the value of national and EU research funding by joint planning, very helpful; and consequently, it took us half the time to launch ERA- implementation and evaluation of national research programmes. NET Neuron's and ERASysBio’s first calls. Member States were invited to identify appropriate themes for Another challenge was that in the beginning, the members of the such activities. various national funding organizations didn't know each other. It took us One result of this process was the establishment of the Joint a while to form an efficient and productive collaborative environment. Programming Initiative on Antimicrobial Resistance (JPIAMR) ERA-NET Now we can more easily launch multi-national initiatives. For example, proposed in 2010 by Sweden and Italy. The aim of the JPIAMR is PathoGenoMics I am involved with five different ERA-NET consortia: PathoGenoMics, to integrate relevant scientific fields across national borders and is a success Industrial Biotech, Neuron, Systems Biology and Plant Genomics; and I to create a common European research agenda with a shared because of two am not an exception. This means that we meet the same colleagues in common vision. main factors: several different networks, which is a great advantage. the people and Since the JPIAMR kick-off meeting in October 2011, eighteen Why is ERA-NET PathoGenoMics so successful? the scope countries have become active partners of the initiative. The ERA-NET PathoGenoMics is a success because of two main factors: the JPIAMR partners have formed the nucleus of a joint vision on how people and the scope of the ERA-NET. In some ERA-NETs the scope to combat antimicrobial resistance. Several steps have already may be too broad, and every call focuses on a different topic. As a been taken to establish JPIAMR as a leading strategic European result, even after four calls, we still have not created a community of research partnership. Infect–ERA, the follow-on ERA-NET to European scientists in that field. PathoGenoMics, is a potential partner with which JPIAMR can In other ERA-NETs the scope may be too narrow, and hence the interest cooperate in the research and treatment of infectious diseases. is limited. The scope of ERA-NET PathoGenoMics is just right. At the Several JPIAMR participants are also members of Infect-ERA. 2010 Tenerife status seminar, we had the participation of researchers involved in the first and second calls, who represented a significant part of the European scientific community in the field. If you are a European scientist in the field of pathogenomics, you have most probably heard about ERA-NET PathoGenoMics. What do you think about the idea that Joint Programming Initiatives (JPI) will focus on more applied research while the ERA-NET should focus on more basic research? I cannot see such a difference between the ERA-NETs and JPIs. I totally ERAERA-NET-NET ERA-NET ERAPathoGenoMicsPathoGenoMics-NET ERAERA-NET-NET PathoGenoMics PathoGenoMicsERA-NET OUTPUT:PathoGenoMicsPathoGenoMicsPathoGenoMics TOP LEVELOUTPUT: PUBLICATIONS TOP LEVEL PUBLICATIONS |100 OUTPUT: TOP LEVEL PUBLICATIONS 101 | OUTPUT: TOP LEVEL PUBLICATIONS OUTCOME: TOP LEVEL PUBLICATIONS OUTPUT:OUTPUT:OUTPUT: TOP LastTOP updated: July TOP2011LEVEL LEVEL LEVEL PUBLICATIONS PUBLICATIONS PUBLICATIONS agree with the final aim of the European Commission to launch JPIs. I understand what they want and it is necessarily to have a more ambitious programme than ERA-NET. It would have been wiser to first evaluate the success of each ERA-NET and to create the JPI based on these conclusions. The way it is now, in some cases, the JPIs compete with the ERA-NETs on funds and budgets within the funding agencies and within the Commission. ERA-NET What do you think are the parameters for the success of ERA-NET PathoGenoMics PathoGenoMics? increases the budget for First and foremost, funding is crucial. The Commission initially invested collaborative €3 million in PathoGenoMics, a sum, which the funding raised by the European partners turned into €42 million. research TheERA PathoGenoMics -budgetNET derived from the Framework programme represents only about 7% of the funds that the consortia invested in research. This funding is earmarked for collaborative European research.PathoGenoMics ERA-NET The lion's share, 93%, is managed by national (and regional) funding organizations, and addresses national (and regional) demands. The ERA-NET framework is an effective way to open the borders of basic research while reducing redundancy in national and regional efforts. ERA-NET increases the budget for collaborative European research, OUTPUT:since the national agencies TOP control the funds LEVEL in coordination with PUBLICATIONS PathoGenoMics other European countries. This is still limited. How do you see the future of ERA-NET PathoGenoMics? I hope that in a few years ERA-NET PathoGenoMics will develop into a JPI or a similar structure and that we will be able to launch calls of €50-60 million. In order to progress, we have to be more ambitious. ERA-NET We should aim at adding more partners from new countries, with each country committing funds in accordance to their scientific contribution. Also, we have to expand our scope in terms of areas of research to PathoGenoMics OUTPUT: TOP LEVEL PUBLICATIONSincorporate approaches such as post-genomics, systems and synthetic biology, and the research of additional pathogens (, parasites) and the systemic relations between them. OUTPUT: TOP LEVEL PUBLICATIONS ERA-NET PathoGenoMics ERA-NET OUTPUT: TOP PathoGenoMicsLEVEL PUBLICATIONS

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PathoGenoMicsOUTPUT: TOP LEVELERA- NETPUBLICATIONS PathoGenoMics ERA-NET OUTPUT: TOP LEVELERA PUBLICATIONS-NET PathoGenoMics OUTPUT: TOP LEVEL PUBLICATIONS PathoGenoMics

OUTPUT: TOP LEVEL PUBLICATIONS OUTPUT: TOP LEVEL PUBLICATIONS ERA-NET ERA-NETERA-NET PathoGenoMics PathoGenoMics ERA-NET PathoGenoMics PathoGenoMicsOUTPUT: TOP LEVEL PUBLICATIONS ERA-NET OUTPUT: TOP LEVEL PUBLICATIONS OUTPUT: TOP LEVEL PUBLICATIONS OUTPUT: TOP LEVEL PUBLICATIONS ERA-NET ERAPathoGenoMics-NET PathoGenoMicsERA-NET OUTPUT: TOP LEVEL PUBLICATIONS PathoGenoMics OUTPUT: TOP LEVEL PUBLICATIONSPathoGenoMics OUTPUT: TOP LEVEL PUBLICATIONS OUTPUT: TOP LEVEL PUBLICATIONS ERAERA-NET-NET PathoGenoMicsPathoGenoMics

|102 103 | ERAERA-NET-NET OUTPUT:OUTPUT: TOP TOP LEVEL LEVEL PUBLICATIONS PUBLICATIONS PathoGenoMicsPathoGenoMics

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Infect-ERA: Taking PathoGenoMics into the including the Joint Programming Initiative (JPI), have come into existence. Infect-ERA plans to cooperate and complement initiatives in the area of infectious disease research, Future treatment and prevention and to consolidate ties with industry, clinical and public health Bruck Serawit, Infect-ERA, Coordinator, application approved organizations towards this end. The ERA-NET PathoGenoMics: "Genome sequencing and functional genomics of human-pathogenic microorganisms", was launched in 2004 under the Sixth Framework Programme. This coordinated action has brought together nine partner countries and six affiliates and, as it winds down in August 2012, it is fair to state that it has been one of the longer term ERA-NETs. This platform for cooperation between European research funding bodies established a successful forum for information exchange between participating member states. This concerted action completed three successful joint transnational calls and funded 34 projects with a budget of over €41 million. After a thorough evaluation of its activities by the participating agencies and scientists, followed by a SWOT analysis conducted during its seventh year of existence, almost all of the existing PathoGenoMics partners as well as several prospective partners decided to join a proposed follow-on ERA-NET on infectious diseases: Infect-ERA. The Infect-ERA proposal was submitted to the European Commission on February 2012 and, has been subsequently approved. It is scheduled to commence activities in January 2013 and end in December 2016. Infect-ERA will build on PathoGenoMics' achievements and network, adopting the principles and mechanisms for the evaluation of joint calls and management of transnational projects. It plans to launch annual joint transnational calls and to provide support for the professional development and independence of young scientists. With a broad scientific scope, Infect-ERA aims at understanding all basic aspects of human infection biology caused by bacteria, fungi, viruses and single cell protozoa. Infect-ERA comprises a larger network of 14 agencies from 11 countries:  The Austrian Science Fund (Austria);  The Agency for Innovation by Science and Technology (Belgium);  The Danish Agency for Science Technology and Innovation (Denmark);  The Forschungszentrum Juelich GmbH (Germany);  The Ministry of Economy and Competitiveness and the National Institute of Health Carlos III (Spain);  The Agence Nationale de la Recherche (France);  The Hungarian Academy of Science and the Hungarian Scientific Research Fund (Hungary);  Chief Scientist Office, Ministry of Health, (Israel);  The National Science Centre and the National Centre for Research and Development (Poland);  The Foundation for Science and Technology (Portugal);  National Authority for Scientific Research (Romania). With an increase of the number of participating agencies, Infect-ERA is expected to increase the impact of joint activities. At the conclusion of Infect-ERA, the European Union will have funded 12 years of scientific cooperation and support activities in the area on infectious diseases. In order to deepen cooperation and ensure sustainability, the consortium will design a long-term model for transnational cooperation during Infect-ERA's lifetime. Furthermore, since the launch of PathoGenoMics, several other European initiatives, |106 107 |

Our Partners Hungary: Austria: Hungarian Academy of Sciences (HAS) Austrian Federal Ministry of Science and Research (BMWF) Contact: Prof. Dr. Béla Nagy | Institute for Veterinary Medical Research, Centre for Contact: Dr. Hemma Bauer | Bundesministerium für Wissenschaft und Forschung (BMWF) Agricultural Research, Hungarian Acadamy of Sciences | Hungária krt. 21 | H-1143, | Abt. Research Policy and Life Sciences Budapest | Hungary Rosengasse 2-6 | A-1014 Wien Email: [email protected] Email: [email protected] Telephone: +36-1-467 4085 The Austrian Research Promotion Agency (FFG) Hungarian Scientific Research Fund (OTKA) Contact: Mag. Nicole Firnberg | Mag. Nora Nikolov | Programmbüro GEN-AU | Contact: Prof. Dr. Levente Emődy | Department of Medical Microbiology and Immnunology, Österreichische Forschungsförderungsgesellschaft mbH | Sensengasse 1 | 1090 Wien | University Medical School of Pécs | Szigeti út 12 | H-7624, Pécs | Hungary Austria Email: [email protected] Email: [email protected] | [email protected] Telephone: +36-72-536 000 ext. 31904 The Austrian Science Fund (FWF) Contact: Dr. Milojka Gindl | Biological and Medical Sciences | Scientific Administrator Israel: Haus der Forschung | 1090 Wien, Sensengasse 1 | Austria The Chief Scientist Office Israeli Ministry of Health (CSO-MOH) Email: [email protected] Contact: Ph.D. Benny Leshem | The Medical Research Administration Chief Scientist Office Finland: Israeli Ministry of Health | 2, Ben Tabai St. | Jerusalem 91010, Israel Academy of Finland (AKA) Email: [email protected] Contact: Dr. Sirpa Nuotio | Academy of Finland PO Box 131 | Hakaniemenranta 6 | 00531 Helsinki, Finland Portugal: Email: [email protected] Portuguese National Science Foundation (FCT) Contact: Dr. Catarina Resende | Fundação para a Ciência e a Tecnologia France: Project Management Transnational Team Institut Pasteur (IP) Av. D. Carlos I, 126, 2º | 1249-074 Lisboa | Portugal Contact: Dr. Philippe Sansonetti | Institut Pasteur Email: [email protected] 28, Rue du Docteur Roux | F-75724 Paris Email: [email protected] Slovenia: Ministry of Education, Science, Culture and Sport (MESCS) Agence Nationale de la Recherche ANR contact: mag. Marta Šabec | Science Division Contact: Dr. Serawit Bruck | Agence Nationale de la Recherche ANR Directorate for Higher Education and Science | Ministry of Education, Science, Culture and 7, rue Watt | F-75013 Paris | France Sport | Masarykova 16 | 1000 Ljubljana | Slovenia Tel: +33 1 73 54 81 70 Email: [email protected] Email: [email protected] Web: http://www.mizks.gov.si/en/ Web: http://www.agence-nationale-recherche.fr Spain: Germany: Ministry of Science and Innovation (MICINN) Bundesministerium für Bildung und Forschung (BMBF) Contact: Mrs. Dr. Rosa Rodríguez Bernabé | Ministry of Science and Innovation (MICINN) Contact: Dr. Christiane Buchholz | Bundesministerium für Bildung und Forschung Life Science Department / Research Projects | D.G. Research | Paseo de la Castellana, 160 Referat 613 / 616 | Hannoversche Straße 28-30 | 10115 Berlin | ES-28071 Madrid Email: [email protected] Email: [email protected] Forschungszentrum Jülich GmbH (FZJ) Contact: Dr. Bülent Genç | Forschungszentrum Juelich GmbH (FZJ), PtJ-BIO Leo-Brandt-Strasse | D-52425 Juelich | Germany Email: [email protected] |108

AFFILIATED MEMBERS:

Latvia: Latvian Council of Science (LCS) University of Latvia | Biomedical Research and Study Centre Ratsupites 1 | LV-1067 Riga

Lithuania: Ministry of Education and Science (MES)

Malta: Malta Council for Science and Technology (MCST)

Norway: The Research Council of Norway (RCN)

Sweden: Swedish Foundation for Strategic Research (SSF)

United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC) |110

ERA-NET PathoGenoMics

Produced by CSO-MOH, Israel Grant number: ERAC-CT-2044-006973

Produced by Produced by CSO-MOH, Israel CSO-MOH, Israel