Research Report 2010 2011 - Helmholtz-Zentrum fÃ¼r ...

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82 SCIENTIFIC REPORTS | Infection and Immunity | Host Pathogen Interactives The host response to viral and bacterial pathogens in experimental models of infection Group A streptococci are prevalent human pathogens capable of causing a variety of diseases ranging from simple pharyngitis to very severe infections, such as necrotizing fascitiis and streptococcal toxic shock syndrome. We have previously shown that strains of mice from various genetic backgrounds differ markedly in their susceptibility to Streptococcus pyogenes. Using these resistant and susceptible mouse strains, we will identify the immunological and molecular mechanisms controlling the resistance or susceptibility to S. pyogenes and design new strategies to enhance resistance in susceptible hosts. Staphylococcus aureus is one of the most important causes of life-threatening bacterial infections in Western countries. The incidence of S. aureus infections has dramatically increased in the last decade, occurring in both, community-acquired and hospital-acquired cases. Despite the substantial progress made in understanding the mechanism employed by S. aureus to persist within the host, few or none studies have addressed the contribution of host factors to the establishment of S. aureus infection. Research in this area has been hampered by the lack of feasible animal models that recapitulate the different aspects of S. aureus infection. We have established an experimental mouse model that sustains a long-term S. aureus infection and, therefore, enables us to dissect the mechanisms underlying the divergent functionality of the host immune response during the different phases of infection. Infl uenza A virus represents one of the most important threats to human health and economics. Thus far, very little is known about host resistance or susceptibility to infl uenza infections. At the HZI, we have established an infection model for infl uenza A H1N1 virus in the mouse and identifi ed signifi cant strain differences in the LD 50 response. We perform comparative studies on the pathogenicity, gene expression patterns in the lung, viral load, and immune response in infected mice from different strains. This information will be used to map quantitative trait loci (QTL) that contribute to infection susceptibility. Potential candidate genes will then be tested by phenotyping combinations of single gene mouse mutants (knock-out, gene trap, classical or ENU-induced) in various genetic backgrounds. Molecular specificity of interspecies and zoonotic pathogen transmissions The mammalian prion protein, PrP C , is able to switch its conformation from a monomeric soluble form into an aggregated transmissible prion state, PrP Sc . Once a prion is introduced into a susceptible host, it triggers a PrP conversion cascade which leads to prion disease. Individual prion strains may lead to distinct prion disease pathologies in one host species. Interspecies transmission will be strongly infl uenced by the extent to which a particular PrPSc conformation is compatible with the primary PrP amino acid sequences of both species. The zoonotic transmission of BSE to humans, and the resistance of humans towards sheep scrapie are well known examples of this process. However, the underlying molecular mechanism of conformational conversion and prion propagation is not at all understood. A major obstacle in the research on prions was the limited availability of samples for prion 3D structure investigations. At the HZI we have established a novel technology to overcome this bottleneck. In particular NMR spectro scopic techniques and other biophysical techniques are used to unravel the structural origin of prion transmission barriers
SCIENTIFIC REPORTS | Infection and Immunity | Host Pathogen Interactives 83 and prion adaptations to new hosts. The 3D structures of mammalian prion associated PrP will be revealed and should provide detailed insight into biophysical mechanisms of the PrP C to PrP Sc conformation conversion.On a broader scope, we have a general interest in the molecular structural investigation of specifi c host:pathogen protein interactions that modulate the interspecies or zoonotic transmissibility of viruses and bacteria. Epidemiological studies in humans to determine environmental and genetic risk factors The causes of human diseases are multi-factorial and consist of environmental, life style, and genetic risk factors. To better assess these factors, we will study the incidence of infectious diseases in humans and determine their genetic and environmental risk factors. To this end, the HZI and other centres of the Helmholtz Association as well as many university partners have initiated a nationwide population-based prospective cohort study, the National (Helmholtz) Cohort. This cohort will contain about 200,000 healthy volunteers from all over Germany. We will administer a questionnaire on acute and chronic infections, vaccination status, and exposure to pet and farm animals. In addition, swabs from the nasal cavity, saliva and feces will be collected and analysed for their microbial communities. The participants of the cohort will be followed for 10-20 years, and we will seek to determine the risk factors which contribute to infectious diseases and to secondary diseases that may be directly or indirectly associated with infections.
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SCIENTIFIC REPORTS 91 Infection and
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PORTRAIT 5 The task of the chemists
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FOREWORD | Prof. Dr. Dirk Heinz 7 F
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OBITUARY | Jürgen Wehland 9 Jürge
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FACTS AND FIGURES 175 Open Day at H
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FACTS AND FIGURES 177 Members of th
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180 IMPRINT Research Report 2010/11
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ISSN 1865-9713 Helmholtz-Zentrum f
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