H. hepaticus: the pathogenesis of IBD

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Idiopathic inflammatory bowel disease (IBD) is a debilitating condition with no known etiology. The pathogenesis of IBD has been studied using targeted gene mutant (knockout) mice that develop chronic intestinal inflammation, which resembles human IBD. It has been shown in several of these knockout mouse models, including T cell receptor alpha beta (TCR alpha beta), interleukin-2 (IL-2), and IL-10 knockout mice, that germ-free conditions protect against the development of IBD. It does not appear that resident intestinal microbiota are sufficient to trigger disease in these animals, but experimental infection with an emerging group of murine bacterial pathogens called enterohepatic Helicobacter species is sufficient to cause IBD. To better understand the pathogenesis of disease in these models, we propose to elucidate the mechanisms by which enterohepatic Helicobacter species cause IBD in knockout mice. Although the adaptive immune system is important in the pathogenesis of IBD, knockout mice lacking adaptive immunity are also susceptible to Helicobacter-associated IBD. For this reason, our proposed studies focus on interactions between enterohepatic Helicobacter species and the innate immune system. Studies will be carried out with Helicobacter hepaticus, the most well characterized enterohepatic Helicobacter species. We and our collaborators have recently determined the complete genome sequence of H. hepaticus ATCC 51449. Taking advantage of the genome sequence, we will identify and characterize candidate bacterial virulence determinants, and generate isogenic mutant strains to test in culture with murine intestinal epithelial cell monolayers and murine macrophages, and in vivo with selected knockout mouse models. These studies will test the hypothesis that discrete bacterial virulence determinants in enterohepatic Helicobacter species elicit proinflammatory responses from the innate immune system, which in the absence of a properly regulated adaptive immune system, lead to IBD. It is hoped that these studies will lead to the development of new strategies for the treatment and the prevention of IBD.