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

发现少数群体特有的幽门螺杆菌 T 细胞表位，可能导致胃癌发病率增加。

• 批准号: 10198572
• 负责人: Erik W Settles
• 金额: $ 43.82万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198572
• 关键词: Age; Alleles; American Indians; Antibiotic Resistance; Antigen Presentation; Arizona; Bacterial Infections; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cancer Diagnostics; Cancer Etiology; Catalogs; Caucasians; Cessation of life; Characteristics; Chronic; Chronic Disease; Code; Communicable Diseases; Communities; Coupled; Development; Digestion; Disease; Duodenal Ulcer; Epitopes; Ethics; Ethnic group; Exhibits; Gastric lymphoma; Gastric ulcer; Gastritis; Genetic; Genetic Variation; Genetic study; Genome; Geographic Locations; Goals; Helicobacter Infections; Helicobacter pylori; Helicobacter pylori induced gastric cancer; Hispanic Americans; Hispanics; Histocompatibility Antigens Class II; Hospitalization; Human; Human Genetics; Human body; Immune; Immune system; In Vitro; Incidence; Individual; Inflammation; Investigation; Laboratories; Lead; Libraries; Life; Liquid substance; Major Histocompatibility Complex; Malignant Neoplasms; Minority; Minority Groups; Morbidity - disease rate; Mus; Native Americans; Navajo; Peptides; Play; Population; Prevalence; Proteins; Proteomics; Publishing; Race; Records; Risk; Role; Socioeconomic Status; Stomach; Stomach Diseases; Survival Rate; Synthesis Chemistry; T cell response; T-Lymphocyte Epitopes; Technology; Therapeutic Intervention; Ulcer; United States; Universities; Variant; Work; cancer survival; carcinogenesis; disorder risk; genetic predictors; genetic variant; genome sequencing; genomic data; high risk population; hospitalization rates; in vitro Assay; malignant stomach neoplasm; member; microbiome components; mortality; mucosa-associated lymphoid tissue lymphoma; novel; pathogen; whole genome

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.

幽门螺杆菌（H.幽门螺杆菌）是一种细菌感染，可以从人体中根除， 但抗生素的耐药性却在上升。这种病原体似乎在健康的人体消化中发挥作用， 是微生物组的一个组成部分，但也与溃疡，胃癌和 胃淋巴瘤已知H.幽门引起的免疫炎症增加了胃炎的风险， 胃癌在美国，患病率因地理位置、种族背景 社会经济地位和年龄。例如，纳瓦霍族成员和西班牙裔人不成比例地 与白人相比，胃癌的发病率更高。胃癌与H.幽门 感染，为什么某些人群在发展胃癌的风险增加，并不完全 明白已发表的研究表明，H。幽门螺杆菌变异，人类MHC类型和T细胞应答， 炎症和胃炎。然而，对H. pylori变异和人类MHC如何呈递 不同的肽对免疫系统的作用尚未进行大规模研究。这项建议旨在 通过检测H.原住民幽门螺杆菌遗传变异 生活在亚利桑那州北方的美国人和西班牙裔美国人，什么肽可以提出共同的土著 美国人和西班牙人的MHC等位基因，以及不同的抗原呈递在H。幽门 诱发炎症和胃癌的发展。我们的总体目标是定义H。幽门蛋白 表位空间，通常可以由美洲原住民和西班牙裔MHC等位基因在体外呈递， 这与由常见的高加索人MHC等位基因呈递的表位形成对比。我们的假设是 有唯一的H。由常见的美洲原住民和西班牙裔MHC II类等位基因呈递的幽门螺杆菌肽 相比于白种人具体来说，我们的目标是SA 1：进行全基因组测序 阁下于pylori菌株，并从预测的pylori菌株中产生PepSeq表位文库。 新的和当前的基因组数据中的编码区，以及SA2：使用 常见的美洲原住民和西班牙裔，以及通常常见的美国MHC II类等位基因。我们期望 通过实验室和合成化学，更好地了解常见的MHC II类的关联， 一个种族群体内的抗原及其与H.高危人群中的幽门螺杆菌。如果成功，这 该项目将在几个层面产生影响：首先，它将为社区提供一套大型的 可能有助于H. pylori和H.幽门螺杆菌胃癌诊断。二是 将为少数人群确定可能导致H风险增加的独特表位。幽门螺杆菌诱导 胃癌治疗干预是可能的那些在高风险的疾病。