Project Summary Background and Innovation. Chronic infections and the inflammation associated with long-term immune activation contribute to carcinogenesis in several tissues, especially gastrointestinal infections. Specifically, Helicobacter pylori infection has been formally recognized as a Type I carcinogen for over many years. More recently, associations between bacterial infections and colorectal cancer have been made (i.e. enterotoxigenic Bacteroides fragilis, pks+ E. coli, F. nucleatum). We use H. pylori as a highly relevant, rigorous and tractable model to investigate an understudied area of host-pathogen interactions, bacterial-driven carcinogenesis. There is an unmet need to understand the dichotomy that exists between immune responses; those that are needed to control infection versus those that drive chronic inflammation. Our published observations indicate that T cell cytokines, especially IL-17 signaling, play a key role controlling H. pylori infection, maintaining the gastric barrier, and preventing exacerbated T and B cell responses (e.g. Th1 responses and antibody production). Importantly, we have found that H. pylori infection outcomes in the absence of IL-17RA are pathologically worse, which is paradoxical to the view that IL-17 is pro-carcinogenic in several tissues. Our data indicate that IL-17RA deficient mice progress to gastric cancer more rapidly. This is clinically relevant for in humans with gastric cancer, higher levels of IL-17RA in gastric tissue is a positive prognostic marker for survival. We will test the hypothesis that IL- 17 and IFNJ (a Th1 cytokine) have divergent roles activating fibroblasts, resulting in protective versus detrimental outcomes, respectively. Our laboratory is uniquely positioned to work at this intersection of inflammation, cancer, and bacterial pathogenesis. This allows us to view the role of the immune response during infection induced cancers through an innovative lens. Two aims are proposed which will utiliz