RESEARCH REPORT 2006/20072008/2009 FOREWORD 04 The Helmholtz Centre for Infection Research (HZI) – a portrait 07 Foreword FOCUS 10 Highlights 2007-2009 RESEARCH REVIEWS 18 Mega-Genomes and Micro-Chemists: New perspectives for the production of bioactive compounds in Myxobacteria 26 Target diagnosis of pathogens SPECIAL FEATURES 32 Ferroplasma acidiphilum: a novel microbe with a unique iron: protein-dominated metabolic apparatus 40 The Internalin Story – lessons from structural infection biology SCIENTIFIC REPORTS 50 INFECTION AND IMMUNITY 52 Microorganisms 54 Structural analysis of virulence factors 55 Pathogenesis of chronic Pseudomonas aeruginosa infections 56 Virulence factors of streptococci and pneumococci 57 Systems biology of Pseudomonas 58 Microbial communication 59 Molecular mechanisms of intracellular traffi cking, survival and persistence of streptococci 60 Pathogenesis 62 Molecular mechanisms of host-cell/pathogen interactions 63 Analysis of the protein networks of early host-pathogen interactions 64 Signalling to actin dynamics 65 The innate immune response to Streptococcus pyogenes in an experimental infection model 66 Systems genetics of infection and immunity 67 Biology of the immune defence 68 Structural and mechanistical analysis of functional amyloids 69 Infl ammation and Immunity 71 Structural analysis of the innate immune system 72 IFN-dependent host-responses upon infection using transgenic reporter mouse models 73 Epigenetic principles of gene regulation 74 Cellular models for infection 75 Mucosal immunity and infl ammation 76 Immune effectors: Molecules, cells and mechanisms 77 Bioinformatics of cellular networks SCIENTIFIC REPORTS 78 Prevention and Therapy 81 Microbial diversity and natural product discovery 82 Medicinal chemistry of antiinfectives 83 Development of new antiinfectives from natural sources 84 Chemical biology of infectious diseases 85 Identifi cation of molecular targets of antiinfectives 86 Antigen delivery systems and vaccines 87 Therapeutic cellular vaccines 88 Molecular diagnostics of microbial pathogens 89 Molecular mechanisms of hepatitis C virus infection and replication 90 GENOME AND HEALTH RESEARCH 91 Inhibitors of protein-ligand interactions 92 Generation and exploitation of DNA sequence data 93 GENES, ENVIRONMENT AND HEALTH 94 Functional genomics and niche specifi ty 95 Metabolic diversity 96 Biofi lm communities in environment and health 97 Communities of pathogenic bacteria 98 Technological Platforms 99 Central animal facility 100 Analytical instruments 101 Gene expression analysis 102 Peptide synthesis 103 Histo-pathology platform 104 Protein expression 105 New Projectgroups 106 Chronic infection and cancer 107 Structural characterization of pathogen defence factors 108 Mammalian prion transmission barriers 109 Development and functional properties of Foxp3+-expressing regulatory T cells 110 Regulation of virulence mechanism implicated in pathogen host cell interactions 111 Intracellular traffi cking of phagosomes and immunity: Lessons from mycobacteria 112 THE FORTHCOMING RESEARCH PROGRAMME “INFECTION AND IMMUNITY” IN PoF II 114 Microbial Pathogenesis 116 Host Resistance and Susceptibility 119 Infl ammation and Immunity 121 Strategies for Prevetion and Therapy 123 Translational Infection Research 124 TWINCORE, Centre for Experimental and Clinical Infection Research GmbH 130 Publications 2007-2009 161 Lectures 2008-2009 FACTS AND FIGURES 166 Facts and Figures 4 PORTRAIT The Helmholtz Centre for Infection Research The Helmholtz Centre for Infection Research in Braun- Infections are always caused by molecular interactions be- schweig lives up to its name: here approximately 250 tween the host and pathogens, and between the pathogens scientists and 350 technical and administrative staff lay themselves. The central elements in these interactions are the foundations for new preventative procedures, diagnostic the proteins involved in the infection. Consequently they approaches, medicines and drugs with which infectious play a key role in the understanding of infectious diseases. diseases can be better cured or more effectively prevented. Microorganisms organise and catalyse their lives with thou- The paths that lead to this goal are as varied as the paths sands of proteins. The goal of infection researchers is not by which the pathogens enter our bodies. Microbiologists only to describe these proteins but also to understand their investigate how bacteria and viruses manage to enter our functions. The proteins on the cell surface, in particular, are bodies, how bacteria communicate with one another and responsible for contact with the host, and the most pertinent how exactly they make us ill. Geneticists investigate our question in this area of research is: how do bacteria manage genetic make-up in a search for reasons why one person to infect us? The arsenal of different pathogenity factors, falls ill with fl u, for example, whilst their neighbour at the with which bacteria, viruses and other microbial pathogens same table does not. Immunologists investigate how orga- interfere with processes within human cells is a modest nisms react to an intruder and resist it. Structural biologists one. However, knowing where these are located and being research the molecular structures of key molecules and their able to name these factors does not mean that they are interactions. Chemists use this knowledge to investigate understood. Proteins are very large molecules with complex and develop new agents that can in turn be employed to structures and it is precisely in these structures that the combat disease. Vaccine researchers have their sights set on secret of their success lies. Scientists at the HZI take a the best way to combat germs using preventative approaches close look at their structure atom by atom. Details of which before an illness occurs. provide fundamental clues as to how they interact with one another and allows a rationale of their involvement in New diagnostic approaches, vaccines and medicines can infection. only be successfully developed when the mechanisms of infectious diseases have been properly understood. A start- Once the structural biologists have familiarised themselves ing point from which researchers at the Helmholtz Centre with these critical regions in the molecular structure the for Infection Research approach the complex network of chemists can begin to put this knowledge to further use. Their “infection” is the cell – both that of the host and that of the goal is to develop tailored molecules that fi t these structures pathogen. One example is opportunistic infections which exactly, and subsequently have the opportunity to interrupt are a problem in hospitals. In a place where patients with an infection. To this end chemists look for natural inhibitors weakened immune systems are treated, bacteria transform or create new synthetic ones, using these to block the func- themselves from unobtrusive companions to dangerous tions of the pathogen proteins in a targeted approach. aggressors. In extreme cases they ensconce themselves permanently in our bodies by forming a so-called biofi lm, The basis for new active agents, which are able to target causing chronic illness under some circumstances. In selected regions of the bacterial proteins, are often natural biofi lms the bacteria are surrounded by a protective sheath agents. These often originate from traditional medicinal that protects them very effectively against attacks from plants, fungi or bacteria. A special role at the HZI is played the immune system or antibiotics. But what has to occur in by the myxobacteria. These live in the soil and defend them- order for a seemingly harmless germ to become an aggres- selves against bacterial competitors using a range of novel sor? How do bacteria communicate with one another and secondary metabolites, substances that are highly active the host? Only when scientists have understood how the when carefully isolated and analysed by natural product pathogens and their host cells interact and the mechanisms chemists and then subsequently developed into antiinfec- behind these interactions can they disrupt the communi- tives. Microbial active metabolites for combating infectious cation between bacteria in a targeted manner. diseases are therefore seen as the optimal starting sub- stances for developing new therapies against infections for use in hospitals and elsewhere. PORTRAIT 5 The task of the chemist in infection research is easily The system-genetic investigation of such interrelations will described but diffi cult to implement: chemists search for lead to new therapeutic approaches. The tools for this are active components that enable myxobacteria to defend not limited to the petri dish, microscope or mouse, but are themselves against other microorganisms or are a basic above all computers. component of a medicinal plant. In these molecules they search for particular structural characteristics and chemi- Research at the Helmholtz Centre for Infection Research cal groups in order to recreate these and even improve their covers a wide fi eld of disciplines ranging from an under- effectiveness. For HZI researchers synthesising or modify- standing of the molecular interactions between pathogen ing natural agents to create potent medicines is a discipline and host to the discovery of new active agents, and methods that bridges the gap between pure research and clinical for disease prevention. Co-operation with the Hannover applications. Medical School has resulted in the