In the focus of the Department of Molecular Biology is the research on the molecular processes that take place in host cells upon infection with bacterial pathogens. Several pathogen models, e.g. Helicobacter pylori, Chlamydia, Salmonella, and Neisseria, serve to advance our understanding of the interplay between pathogens and the host cells. Emphasis is placed on an understanding of principle bacterial virulence mechanisms, receptor-mediated interactions with target cells, pathogen-induced signalling events, and the mechanisms relevant for intracellular pathogen accommodation. Furthermore, we are concerned with the analysis of mechanisms underlying chronic infection and its consequences for inflammation, cell damage, cellular senescence and the development of cancer. Hence, our particular interest is also in the H. pylori model where we aim to understand pathogen-specific immune response mechanisms and to assess strategies in clinical settings towards the development of an effective vaccine against H. pylori. To achieve our scientific goals we employ a spectrum of advanced methodologies enabling pathogen genetics, high-resolution live cell microscopy, as well as functional gene analysis using RNA interference and other global approaches in genomics and proteomics.

Within the framework of the INCA project we will focus our efforts to the following areas: We will investigate the mutagenic effects of H. pylori strains in vivo, using suitable transgenic mouse models, that facilitate the detection of mutagenic effects in the gastric mucosa and the analysis of mechanisms responsible for early events involved in the promotion of gastric precancerous lesions. Important goals include the characterization, (i) of DNA mutations and lesions induced by the infections, and (ii) of the impact of an infection on the function of the host DNA repair machinery. We will also aim towards an understanding of the processes leading to pathogen-induced chromosomal damage using infected cell culture models. Specifically, we will (i) construct a panel of recombinant cell lines harbouring mutationally sensitive target sequences and indicator genes, (ii) assess the effect of infection at the level of oxidative responses and mutational activity, and (iii) investigate the involvement of bacterial, viral, and cellular factors in the generation of cellular responses and DNA damage. Finally, we will investigate the role of Toll-like and NOD receptors in the induction of inflammatory responses in human cells infected with H. pylori. Also to study Helicobacter and epithelial cell signalling with the objective of identifying inhibitors of relevant pathways that could prevent Helicobacter associated disease. In the context of our extensive experience with the RNAi technology and our function as the coordinator of the FP6 Integrated Project RIGHT, dedicated to developing this technology for therapeutic treatments, we will be involved in the INCA technology platform and will provide direct access to technology and expertise available in at our institutional RNAi technology platform. This will provide the INCA consortium with a unique advantage with respect to exploiting this technology. RNAi will be applied to human or mouse cultured cells by transfecting synthetic small interfering RNAs (siRNAs) or by lentiviral transfer of shRNA transcription cassettes. Both techniques may be assisted through pipetting robots in order to maximize reproducibility, throughput, and cost-effectiveness of the process.

Backert,S. and Meyer,T.F. (2006). Type IV secretion systems in bacterial virulence. Curr Opin Microbiol 9, 207-217. Becker,D., Selbach,M., Rollenhagen,C., Bamberg,S., Meyer,T.F., Mann,M., and Bumann,D. (2006). Robust Salmonella metabolism limits possibilities for new antimicrobials. Nature 16, 303-307. Lebrun,A.-H., Wunder,C., Hildebrand,J., Churin,J., Zähringer,U., Lindner,B., Meyer,T.F., Heinz,E., and Warnecke,D. (2006). Cloning of a Cholesterol-alpha-Glycosyltransferase from Helicobacter pylori. J. Biol. Chem. Moese,S., Selbach,M., Brinkmann,V., Karlas,A., Haimovich,B., Backert,S., and Meyer,T.F. (2006). The Helicobacter pylori CagA protein disrupts matrix adhesion of gastric epithelial cells by dephosphorylation of vinculin. Cell. Microbiol. in press. Wunder,C., Churin,J., Winau,F., Warnecke,D., Vieth,M., Lindner,B., Zähringer,U., Mollenkopf H.J.,H.E., and Meyer,T.F. (2006). Cholesterol glucolysation promotes immune evasion by Helicobacter pylori. Nature Medicine 12, 1030-1038.