Discovery of H. pylori T cell epitopes unique to minority populations that could contribute to increased gastric cancer rates. - 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.
