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. pylori）是一种细菌感染，大多数人都可以将其从人体中根除。 然而，抗生素的耐药性正在上升。该病原体似乎在健康的人类消化中发挥着作用，因为 微生物组的一个组成部分，但也与溃疡、胃癌和 胃淋巴瘤。众所周知，幽门螺杆菌引起的免疫炎症会增加胃炎和胃炎的风险。 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口比例不成比例。 与白种人相比，胃癌发病率较高。虽然胃癌与幽门螺杆菌有关 感染，为什么某些人群患胃癌的风险增加，尚不完全清楚 明白了。已发表的研究表明幽门螺杆菌变异、人类 MHC 类型和 T 细胞反应在 炎症和胃炎。然而，对幽门螺杆菌变异以及人类 MHC 如何存在的研究 不同的肽对免疫系统的影响尚未得到大规模研究。该提案旨在 通过检查本地人中幽门螺杆菌遗传变异来研究这种传染病与慢性疾病的相互作用 居住在亚利桑那州北部的美国人和西班牙裔美国人，常见的原住民可以呈现哪些肽 美国人和西班牙人的 MHC 等位基因，以及差异抗原呈递如何在幽门螺杆菌中发挥作用 诱发炎症和胃癌的发展。我们的总体目标是定义幽门螺杆菌蛋白 美洲原住民和西班牙裔 MHC 等位基因在体外通常可以呈现的表位空间，并且 将此与常见白种人 MHC 等位基因呈现的表位进行对比。我们的假设是 常见的美洲原住民和西班牙裔 MHC II 类等位基因呈现独特的幽门螺杆菌肽 与更多的白人人口相比。具体来说，我们的目标是 SA1：进行全基因组测序 从美洲原住民中分离出幽门螺杆菌菌株，并根据预测生成 PepSeq 表位文库 新的和当前的基因组数据中的编码区和 SA2：使用以下方法执行 MHC-PepSeq 结合研究 常见的美洲原住民和西班牙裔，以及普遍常见的美国 MHC II 类等位基因。我们期望 通过实验室和合成化学更好地理解常见 MHC II 类的关联 一个种族群体内的抗原及其与高危人群幽门螺杆菌的相互作用。如果成功的话，这 项目将在多个层面产生影响：首先，它将向社区提供大量 潜在的 CD4+ T 细胞表位可协助幽门螺杆菌和幽门螺杆菌胃癌的诊断。其次，它 将识别少数群体的独特表位，这些表位可能导致幽门螺杆菌感染风险增加 胃癌。对于疾病高危人群来说，治疗干预是可能的。