Helicobacter pylori (H. pylori) is a bacterial infection which can be eradicated from the human body by most antibiotics, though, resistance is on the rise. The pathogen seems to play a role in healthy human digestion, as a component of the microbiome, but is also associated with development of ulcers, stomach cancer and stomach lymphomas. It is known that H. pylori-induced immune inflammation elevates the risk for gastritis and gastric cancer. In the United States (US), prevalence varies by geographic location, ethnic background, socioeconomic status, and age. For example, Navajo Nation members and Hispanics have disproportionately high rates of stomach cancer compared to Caucasians. While stomach cancer is associated with H. pylori infection, why certain populations are at increased risk at developing gastric cancer are not completely understood. Published studies suggest a role for H. pylori variation, human MHC types, and T cell response for inflammation and gastritis. However, the investigation into H. pylori variation and how human MHC present different peptides to the immune system have not been investigated at large scale. This proposal seeks to investigate this infectious-chronic disease interface by examining H. pylori genetic variation among Native Americans living in Northern Arizona and Hispanics, what peptides can be presented by common Native American and Hispanic MHC alleles, and how differential antigen presentation could play a role in H. pylori induced inflammation and gastric cancer development. Our overall goals are to define the H. pylori protein epitope space that could be commonly presented by Native American and Hispanic MHC alleles in vitro, and to contrast this with epitopes that are presented by common Caucasians MHC alleles. Our hypothesis is that there are unique H. pylori peptides presented by common Native American and Hispanic MHC class II alleles compared to the larger Caucasian population. Specifically, we aim to SA1: Perform whole genome sequencing of H. pylori strains isolated from Native Americans and generate PepSeq epitope libraries from predicted coding regions in the new and current genomic data, and SA2: Perform MHC-PepSeq binding studies using common Native American and Hispanic, as well as, generally common USA MHC class II alleles. We expect to better understand, through laboratory and synthetic chemistry the association of common MHC class II antigens within an ethic group and their interaction with H. pylori from high-risk populations. If successful, this project will have an impact at several levels: First, it will make available to the community a large set of potential CD4+ T cell epitopes that could assist in H. pylori and H. pylori gastric cancer diagnostics. Second, it will identify unique epitopes to a minority population that could contribute to increased risk of H. pylori induced gastric cancer. Therapeutic intervention is possible for those at high disease risk.