H. pylori has been called the most common infectious disease of humans in the world today. Worldwide, between 50-100% of people are infected with H. pylori, but only a minority of those develop clinical signs of disease. Almost 2 decades of research have resulted in a general consensus that both host and bacterial factors contribute to disease, but the specific bacterial factors involved and the mechanisms whereby they promote colonization and induce severe manifestations of disease are not well understood. The overall goal of this project is to investigate these mechanisms. In the first funding interval we developed a mouse model of severe disease in which the contributions of host and bacterial factors to severe manifestations of disease can be evaluated. We utilized this model to determine the T cell subsets and cytokines that contribute to disease, we identified one bacterial factor, lipopolysaccharide O-antigen, that induces a deleterious host response and thus contributes to the outcome of disease, and we identified an H. pylori promoter, cagl5, that is upregulated in vivo and likely represents a new virulence factor. In this renewal, we will investigate the roles of O-antigen and cagl 5 in H. pylori pathogenesis, and use a newly-developed promoter trap to identify H. pylori genes that are upregulated in vivo. The 3 specific aims are:
Specific aim 1 : To test the hypothesis that cag15 has a role in survival of H. pylori in vivo, and to determine the role of the cagl5 gene product in colonization and disease.
Specific aim 2 : To use a ureB reporter construct for promoter trapping, to identify novel colonization factors that are induced by growth in vivo, and to test the hypothesis that upregulated genes are essential for or facilitate colonization by and/or gastritis due to H. pylori.
Specific aim 3 : To test the hypothesis that the polysaccharide moiety of H. pylori lipopolysaccharide induces gastritis by receptor-mediated activation of antigen presenting cells. Successful completion of these aims will lead to improved understanding of the pathogenesis of H. pylori associated disease and provide a foundation for development of novel therapies.
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