The role of Th17 cytokines in H.pylori infection

Th17细胞因子在幽门螺杆菌感染中的作用

• 批准号: 8264704
• 负责人: HOLLY Marie Scott ALGOOD
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264704
• 关键词: A Mouse; Address; Afghanistan; B-Lymphocytes; Bacteria; Carcinogens; Cells; Chronic; Chronic Gastritis; Conflict (Psychology); Country; Data; Developing Countries; Disease; Epithelial Cells; Equilibrium; Far East; Gastric Adenocarcinoma; Gastric mucosa; Gastritis; Gram-Negative Bacteria; Growth; Health; Helicobacter Infections; Helicobacter pylori; Host Defense; Immune; Immune response; Immune system; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Iraq; Korea; Lead; Link; Location; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Middle East; Modeling; Mus; Neutrophil Activation; Neutrophil Infiltration; Outcome; Pathology; Peptic Ulcer; Persons; Phenotype; Play; Population; Prevalence; Psoriasis; Receptor Signaling; Regulatory Pathway; Relative (related person); Rheumatoid Arthritis; Role; Signal Transduction; Site; Skin; Stomach; T cell response; T-Lymphocyte; Travel; United States; Vaccines; Veterans; Wild Type Mouse; World Health Organization; adverse outcome; antimicrobial; body system; cell motility; cell type; chemokine; cytokine; design; driving force; extracellular; granulocyte; immunopathology; in vivo; interest; interleukin-22; malignant stomach neoplasm; neutrophil; pathogen; public health relevance; receptor; research study; respiratory; response; tissue culture

DESCRIPTION (provided by applicant): The immune response to Helicobacter pylori is ineffective in clearing infection, but in most cases it successfully restricts bacterial proliferation, and most H. pylori-infected persons remain asymptomatic. A T helper 17 response to H. pylori is required for control of infection, but also controls inflammation and immune cell migration. Our own studies have identified IL-17 signaling as an essential regulator of the host response to H. pylori and a strong candidate for a link between T cell activity and effector functions. The mechanisms by which IL-17 regulates bacterial- host interactions are not completely understood. Addressing the role of T helper 17 cytokines, including IL-17A, IL-17F, and IL-22, during H. pylori infection is particularly interesting because H. pylori is a persistent infection which can lead to adverse outcomes including peptic ulcers and gastric cancer. It is well accepted that IL-17 induces chemokine expression in epithelial cells for the recruitment of neutrophils, but since the receptor for IL-17, IL-17RA, is expressed on many cell types, including epithelial cells, granulocytes, and lymphocytes, its effects are even more widespread. The specific aims are designed to elucidate the relative contributions of cytokines produced by Th17 cells to the epithelial cell and neutrophil response and specifically in control of H. pylori infection and gastritis. We will (1) investigate the role of IL-17 and IL-22 cytokines in stimulating gastric epithelial cell expression of antimicrobial products during H. pylori infection. Moreover, we will (2) determine the role of IL-22 in control of bacterial colonization and maintenance of barrier function during H. pylori infection, and (3) determine whether IL-17 has a direct effect on neutrophil activation during H. pylori infection. In addition to enhancing our understanding of H. pylori infection, these experiments will contribute to our understanding of the immune pathology associated with mucosal infections and immune- mediated diseases, such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis. PUBLIC HEALTH RELEVANCE: The prevalence of H. pylori infection is higher in the Far East, Middle East, and many developing countries than in the United States. Persons from the United States who travel to these parts of the world may acquire H. pylori infection while overseas. Therefore, it seems likely that we may see many new cases of H. pylori infection and an increase in H. pylori-associated illnesses in the United States as Veterans return from sites of conflict in Afghanistan, Iraq, and countries in the Far East such as Korea. Advancement in our understanding of the immune response to H. pylori will broadly impact the health of Veterans by bringing us closer to an effective H. pylori vaccine. Moreover, understanding the role of inflammatory cytokines during the immune response to H. pylori infection in the gastric mucosa should increase our understanding of the immunopathology during immune-mediated diseases such as inflammatory bowel disease and rheumatoid arthritis.

描述（由申请人提供）： 对幽门螺杆菌的免疫反应在清除感染方面无效，但是在大多数情况下，它成功限制了细菌增殖，并且大多数幽门螺杆菌感染的人仍然无症状。控制感染需要对幽门螺杆菌的T助手17反应，但也控制炎症和免疫细胞迁移。我们自己的研究已经确定IL-17信号传导是宿主对幽门螺杆菌反应的重要调节剂，并且是T细胞活性与效应子功能之间联系的有力候选者。 IL-17调节细菌宿主相互作用的机制尚未完全了解。在幽门螺杆菌感染期间，解决T助手17细胞因子（包括IL-17A，IL-17F和IL-22）在内的作用特别有趣，因为幽门螺杆菌是一种持续的感染，可能导致不良发生，包括消化溃疡和胃癌。众所周知的是，IL-17在上皮细胞中诱导中性粒细胞募集的趋化因子表达，但是由于IL-17，IL-17RA的受体在许多细胞类型上表达，包括上皮细胞，颗粒细胞和颗粒细胞和淋巴细胞，其影响甚至更广泛。该特定目的旨在阐明Th17细胞产生的细胞因子对上皮细胞和中性粒细胞反应的相对贡献，并特别是控制幽门螺杆菌感染和胃炎。我们将（1）研究IL-17和IL-22细胞因子在幽门螺杆菌感染期间抗菌产物刺激胃皮细胞表达中的作用。此外，我们将（2）确定IL-22在幽门螺杆菌感染期间控制细菌定植和维持屏障功能的作用，（3）确定IL-17在幽门螺杆菌感染过程中是否对中性粒细胞激活有直接影响。除了增强我们对幽门螺杆菌感染的理解外，这些实验还将有助于我们对与粘膜感染和免疫疾病相关的免疫病理学的理解，例如牛皮癣，炎症性肠病和类风湿性关节炎。 公共卫生相关性： 远东，中东和许多发展中国家的幽门螺杆菌感染的患病率高于美国。来自美国前往世界这些地区的人可能会在海外收到幽门螺杆菌感染。因此，随着退伍军人从阿富汗，伊拉克，伊拉克的冲突场所以及韩国等远东地区的冲突场所返回，我们似乎可能会看到许多新的幽门螺杆菌感染病例和幽门螺杆菌相关疾病的增加。我们对幽门螺杆菌免疫反应的理解的进步将通过使我们接近有效的幽门螺杆菌疫苗，从而广泛影响退伍军人的健康。此外，了解在胃粘膜中对幽门螺杆菌感染的免疫反应中炎症性细胞因子的作用应增加我们对免疫介导的疾病（如炎症性肠病和类风湿关节炎）期间对免疫病理学的理解。