DESCRIPTION (provided by applicant): Helicobacter pylori is the dominant member of the gastric microbiota in a majority of the world's population. H. pylori colonization can lead to protection from some pro-inflammatory diseases such as allergic airway disease, but also can lead to significant detrimental outcomes, including gastritis, peptic ulcers and gastric cancer. Infection with H. pylori is the single most common ris factor of gastric cancer; for this reason, H. pylori was defined by the World Health Organization as a Class I carcinogen. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. The long-term chronic pro-inflammatory response to H. pylori is believed to drive or initiate the pathways which lead to the adverse outcomes of colonization including chronic gastritis, intestinal metaplasia, and gastric cancer. We have accumulated preliminary data that strongly implicate interleukin-21 (IL-21), a cytokine produced by many subsets of activated CD4+ T cells, as a critical driver of adverse consequences of H. pylori colonization and infection. There is a fundamental gap in our understanding of how many pro-inflammatory molecules lead to these detrimental outcomes. The major goal of this application is to investigate the mechanisms by which IL-21 regulates the immune response to H. pylori, by primarily utilizing mouse models that focus on the primary detrimental outcome of infection, gastritis. A second goal is to determine the impact of IL-17 and IL-21 immunotherapies on gastritis. Moreover, organoids and human biopsies will be used to investigate IL-21 activated pathways at various steps along the gastric precancerous cascade. In this proposal, the specific aims are designed to elucidate the mechanism by which IL-21 modulates both immune and non- immune cell responses. Our central hypothesis is that IL-21 is a master regulator of the inflammatory response during H. pylori infection, thereby driving detrimental outcomes (such as gastritis). The Specific Aims are: 1. To investigate the mechanisms by which IL-21 regulates pro-inflammatory T cell priming and activation during H. pylori infection. 2. To determine the contributions of IL-21 in dendritic cell function during H. pylori infection. 3. To elucidate the contribution of IL-21-mediated epithelial cell responses to control of gastritis and H. pylori colonization. This research will also inform myriad of other infectious and chronic inflammatory disorders for which IL-21 is increasingly recognized to play a central role. Defining mechanisms through which H. pylori induces gastric cancer may provide important insights into other malignancies that arise from inflammatory foci. Moreover, the proposed studies will generate new insights into the fundamental mechanisms involved in the development of chronic inflammation.

PUBLIC HEALTH RELEVANCE: Colonization with the bacterium Helicobacter pylori can lead to detrimental outcomes for the human host including gastritis, peptic ulcers and gastric cancer. The risk of developing one of these adverse outcomes increases with smoking, a high salt diet and stress; factors which are increased in our Veterans compared to the general population. Moreover, the magnitude and type of immune response elicited by H. pylori impacts the outcome. The work proposed here is designed to elucidate the mechanisms by which a pro-inflammatory molecule (Interleukin-21) regulates the immune response to H. pylori. This project will: i). improve our understanding of the immunological mechanisms that govern the long-term consequences of chronic H. pylori colonization, and ii). identify cellular targets for pharmaceutical intervention to prevent adverse consequences of colonization.