RESEARCH REPORT 2006/20072010/2011 FOREWORD 04 The Helmholtz Centre for Infection Research – a portrait 07 Foreword 08 Orbituary – Jürgen Wehland FOCUS 12 The German Centre for Infection Research (DZIF) – a great chance for the HZI 15 Highlights 2010-2011 RESEARCH REVIEWS 22 Frontier runners of Hepatitis C Virus 30 The aging of the immune system: challenges and perspectives 36 Novel nanoparticle-based technology platform for the delivery of vaccine antigens 42 Mycobacterial phagosomes and innate immunity SPECIAL FEATURES 48 Where would we be without DNA sequences? 52 Nuclear magnetic resonance spectroscopy, a major player in the arsenal of platform technologies available in the HZI 60 International cooperation of Helmholtz Centre for Infection Research with India and China: a success story SCIENTIFIC REPORTS 64 INFECTION AND IMMUNITY 67 Microbial Pathogenesis 69 Structural analysis of virulence factors 70 Virulence factors of streptococci and pneumococci 71 Molecular mechanisms of intracellular traffi cking,survival and persistence of streptococci 72 Analysis of protein networks induced by early host-pathogen interactions 73 Structural and mechanistical analysis of functional amyloids 74 Microtubule dynamics and bacterial pathogenesis 75 Function and regulation of Yersinia virulence factors 76 Structural characterisation of pathogen defence factors 77 Mycobacterial phagosomes and immunity 78 Molecular mechanisms of host-cell pathogen interactions 79 Signalling to actin dynamics 80 Generation and exploitation of DNA sequence data 81 Host Pathogen Interactions 84 Pathogenesis of chronic Pseudomonas aeruginosa infections 85 Unravelling mechanisms of host defence against Gram-positive pathogens in the mouse model 86 Microbial communication 87 Systems genetics of infection and immunity 88 The structural basis of mammalian prion transmission barriers 89 Biofi lm communities 90 Metabolic diversity SCIENTIFIC REPORTS 91 Infection and Immunity 92 Development and functional properties of Foxp3+ regulatory T cells 93 Mucosal immunity and infl ammation 94 Immuneffectors: molecules, cells and mechanisms 95 Interferons in viral defence and immunity 96 Cell-death mechanisms in immunity 97 Infl ammation and regeneration 98 Cellular models for infection 99 Strategies for Prevention and Therapy 102 Molecular mechanisms of infection and replication in the hepatitis C virus 103 Interaction between innate and adaptive immunity 104 Antigen delivery systems and vaccines 105 Chronic infection and cancer 106 Therapeutic cellular vaccines 107 Molecular diagnostics of mircobial pathogens 108 Pharmaceutical Research 110 Microbial diversity and natural product discovery 111 Medicinal chemistry of natural products 112 Chemical biology of infectious disease 113 Identifi cation of molecular targets of antiinfectives 114 New Project Groups 115 Regulation and herpesviral immune modulation of toll-like receptor signalling 116 Systems immunology 117 The National (“Helmholtz“) Cohort 118 Immune aging 119 Development of novel diagnostic and therapeutic tools for tuberculosis control and prevention 120 Exploring and exploiting microbial proteomes 121 POF II INDEPENDANT RESEARCH 122 Functional genomics and niche specifi ty 123 Structural biology of the cytoskeleton 124 Structural analysis of the innate immune system 125 TECHNOLOGICAL PLATFORMS 126 Central animal facility 127 Recombinant protein expression 128 Gene expression analysis 129 Peptide synthesis 130 Histo-pathology platform 131 Analytical instruments 132 The Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) 138 TWINCORE, Centre for Experimental and Clinical Infection Research GmbH 148 Publications 2010-2011 FACTS AND FIGURES 172 Facts and Figures 4 PORTRAIT The Helmholtz Centre for Infection Research Our name refl ects the scientifi c programme: At the Infections are always caused by molecular interactions Helmholtz Centre for Infection Research in Braunschweig between humans and pathogens and between the pathogens approximately 350 scientists and 350 employees from themselves. Central element of this interplay are the technology and administration lay the foundations for new proteins involved in infections. These consequently play a prevention methods, diagnostic procedures, medicines and key role in the comprehension of infectious diseases. The active agents with which infectious diseases can be better microorganisms organise and catalyse their life with treated or more effectively prevented. The paths that lead to thousands of proteins. The goal of infection researchers is this goal are as varied as the paths by which the pathogens not only to describe these proteins but also to understand enter our bodies. Microbiologists investigate how bacteria their functions. The proteins on the cell surface, in particu- and viruses manage to enter our bodies, how bacteria lar, are responsible for the contact with the host – and the communicate with one another and how exactly they make question hanging over the research remains: how do bacteria us ill. Geneticists investigate our genetic make-up in search manage to infect us? The arsenal of these different pathogen- of reasons why one person falls ill with fl u, for example, ity factors, with which bacteria, viruses and other microbial whilst his neighbour does not. Immunologists investigate pathogens interfere with the process of human cells is a how organisms react to an intruder and resist it. Structural modest one – however, knowing where these are located and biologists research the molecular structures of key mole- being able to name these factors does not yet mean that they cules with all of their interactions. Chemists use this are understood. Proteins are very large molecules with knowledge to investigate and develop new agents that can complex structures and it is precisely in these structures that in turn be employed to combat pathogens. Vaccine research- the secret of their success lies. The scientists at the HZI take ers have their sights set on the best way to combat germs: a close look at their structure - atom for atom. They look for they aim to prevent these from making us ill at all. niches and hooks with which they brush alongside one another, cling to and release one another. New diagnostic approaches, vaccines or medicine can only be successfully developed when the mechanisms of Once the structural biologists have familiarised themselves infectious diseases have been properly understood. A with these decisive parts of the molecular structure the starting point from which researchers at the Helmholtz chemists can begin to put this knowledge to further use. Centre for Infection Research approach the complex Their goal is to develop tailored molecules that fi t this network of “infection” is the cell - both that of the host and structure exactly - and subsequently have the opportunity that of the bacteria. One example: opportunistic infections. to interrupt an infection. To this end chemists look for These are a problem in hospitals. In a place where patients natural inhibitors or create new synthetic ones, using these with weakened immune systems are treated, bacteria to block the functions of the pathogen proteins in a targeted transform themselves from unobtrusive companions to approach. dangerous aggressors. In extreme cases they ensconce themselves permanently in our bodies by forming a The basis for new active agents, which can then attack the so-called biofi lm, causing chronic illness under certain weak points of the bacterial proteins, are often natural circumstances. In biofi lms the bacteria are surrounded by a agents. These originate in traditional, recently rediscovered protective sheath that protects them very effectively against healing plants, from fungi or bacteria. A special role in the attacks from the immune system or antibiotics. But what HZI research is played by the myxobacteria. These live in has to occur in order for a seemingly harmless germ to the soil and defend themselves against bacterial com petitors become an aggressor? How do bacteria communicate with with a range of chemical substances - substances that are one another and the host? Only when scientists have highly effective when precisely analysed by infection understood how the pathogens and their host cells interact researchers and then developed into medicines. Microbial and which are the mechanisms behind these interactions active agent principles for combating infectious diseases they can disrupt the communication between bacteria in a are therefore seen as the optimal initial substances for targeted manner. developing new therapies against bacteria for use in hospitals. PORTRAIT 5 The task of the chemists in infection research is easily imperviously to an infection. In this, the genes infl uence described but diffi cult to implement: chemists search for one another, with the consequence that a defective gene effective components that enable myxobacteria to defend may be compensated by another gene or defects in genetic themselves against other microorganisms or turn a plant material reinforce one another. The system-genetic investi- into a healing plant. And in these molecules they search for gation of such interrelations will lead to new therapeutic decisive structural characteristics and chemical groups in approaches. The instruments for this are not limited to the order to recreate these and even improve their effective- petri dish, microscope or mouse, but are above all computers. ness. Synthesising or modifying natural agents to create potent