Molecular basis of Helicobacter hepaticus-induced pathogenesis in murine models of inflammatory bowel diseases

Chronic inflammatory diseases of the human gut (IBD), Crohn's disease and ulcerative colitis, are probably the result of a misdirected response of the gut against colonizing bacteria. The microbial causes of IBD and its common malignant sequelae are poorly understood. The project studies the role of microbial factors in the pathogenesis of IBD in the model of murine Helicobacter hepaticus infection. H. hepaticus , an enterohepatic Helicobacter species and a close relative of the human pathogen, Helicobacter pylori , causes IBD in a large number of immunocompromised mouse strains. The H. hepaticus model offers the opportunity to characterize a system where the genomes of host and pathogen are both known and genetically manipulatable. Based on the genome sequence of H. hepaticus which we recently published, we will investigate the role of bacterial components in the initiation of IBD by constructing isogenic mutants in putative H. hepaticus virulence factors and characterizing them in diverse in vitro (cell culture) and in vivo (animal) model systems. The study focusses on the HHGI1 genomic island, a putative pathogenicity island of H. hepaticus which encodes components of a type IV secretion system. The long term goal of the project is the elucidation of pathogenic mechanisms by which H. hepaticus induces IBD-like lesions in mice. This will be done in close collaboration with other groups in the SFB621 which study the role of host genetic factors in the development of intestinal inflammation/tolerance.