The role of T cell derived cytokines in Helicobacter pylori

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Project Summary Helicobacter pylori infection can serve as a highly relevant, rigorous and tractable model to investigate an understudied area within the host-pathogen interactions, bacterial-driven carcinogenesis infection. Helicobacter pylori infection is the number one risk factor for the development of gastric cancer. Interestingly, while Helicobacter pylori colonization is very common, only a small percentage of infected people will go on to develop gastric cancer as a result of colonization. Nevertheless, this equates to a significant number of gastric cancer patients. Current estimates provided by the American Cancer Society, are that there will be 27,600 new cases of gastric cancer diagnosed and an estimated 11,010 deaths attributed to the disease in 2020. Differences in how a host responds to the infection can impact the level of inflammation and chronic oxidative stress which contribute to gastric carcinogenesis. This proposal is based on the following scientific premise: 1. The interleukin 17 signaling pathway has been implicated in driving inflammation due to its ‘pro-inflammatory’ activities; contributing to immunopathology through signaling epithelial cells to recruit neutrophils and potentiate oxidative stress and 2. IL-17 receptor signaling also contributes to limiting chronic inflammation within the gastric mucosa during H. pylori infection – which directly challenges the basic understanding of the IL-17 pathway. In this application, we propose an experimental strategy that will identify the cell-specific mechanisms by which IL-17RA and IL-17RC regulate the adaptive immune response during H. pylori colonization. We hypothesize that H. pylori- mediated chronic inflammation and carcinogenesis is controlled by cell-specific, TRAF-dependent IL-17 signaling. Further, that IL-17R signaling through either RA or RC is necessary for a pro-inflammatory response in some cell types (i.e. epithelial cells) but plays an underappreciated, anti-inflammatory role in CD4+ T lymphocyte activation. Further, we propose a strategy that will investigate how other factors in the gastric microenvironment might impact IL-17 signaling through modulating IL-17R signaling complexes and TNF receptor associated factors (TRAFs) which orchestrate signaling and subsequent transcription and proliferation. Our research approach will determine if these dichotomous roles of IL-17R contribute to the host’s ability to control H. pylori infection and inflammation without the development of gastric cancer. This project will provide an understanding of how IL-17 receptor signaling affects the development of carcinogenesis in both a mouse model, as well as in human specimens using an existing tissue array. These studies will help create tools which can be leveraged for future studies to identify biomarkers of cancer progression, investigate how immune- therapies or vaccines might affect outcomes of H. pylori colonization. Ultimately, these tools could help to determine how supplemental immunotherapies might enhance bacterial clearance, reduce development of antimicrobial resistance and reduce the risk of gastric cancer.