The overall goal of this purpose is the identification of host, microbial and environmental factors that modulate the gastric mileau to chronic Helicobacter infection in the mouse and gerbil models. Helicobacter pylori infection has been unequivocally linked epidemiologically to gastric cancer, but risk factors other than H. pylori infection are important in determining overall gastric cancer risk. For example, little is known about how concurrent infections affect host immune responses to H. pylori infection. This knowledge would be of considerable importance in rational design and optimization of H. pylori vaccination protocols and treatment programs. Clinical and epidemiologic studies suggest that the development of atrophic gastritis intestinal metaplasia and dysplasia represent essential steps in the cascade of events leading to gastric cancer. Studies by our group using H. felis (and more recently H. pylori) infection of C57BL76 and INS/GAS mice have led to the development of mouse models of severe body gastritis, atrophy, and intestinal metaplasia. Dysplasia and invasion of the muscularis mucosa and submucosa vasculature in these mice are features compatible with gastric adenocarcinoma. Moreover, we have established models for examining the influence of specific candidate bacterial factors (cag, copA, fdrA) host factors (iNOs, p53, toll receptors, gastrin) and environmental factors (high salt diet and cholesterol) on helicobacter-associated gastritis. In proposed studies we will assess the hypothesis that the progression to gastric cancer is influenced strongly by chronic oxidative stress and specific mutations in the infected host. H. pylori gene transcription profiles and the effect of concurrent infection on in vivo transcriptomes will be studied in the H. pylori gerbil model. We have shown that the Th1/Th2 gastric cytokine profile with concurrent modulation of Helicobacter gastritis can be influenced by co-infections with protozoa and helminthes Increasing evidence suggests that the acquired immune response to gastric Helicobacter spp. plays a central role in mediating gastric pathology. It has been suggested that the balance between pathogenic effector T cells and antigen induced regulator cells is a critical factor in determining whether the host develops inflammatory pathology. We hypothesize that regulatory T cells may play an important role in limiting Hp-induced pathology in the stomach. Determining the role of regulatory T cells responses in limiting Hp-induced gastric pathology could have important implications for the development of novel therapeutic strategies. Specifically, 1) Does increased inflammation increase the risk of mutagenesis and tumor induction via oxidative stress in H. pylori infected specified mouse models;2) Determine the transcription profiles of H. pylori in the stomach of Mongolian gerbil and the effect of co-infection with Brugia pahangi;3) To study how the host immune response modulates H. pylori pathogenesis and specifically evaluate the role of regulatory T cells in limiting H. pylori-induced gastric pathology.
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