The role of T cell derived cytokines in Helicobacter pylori

项目摘要 幽门螺杆菌感染可以作为一个高度相关、严格和易处理的模型来研究 未研究区域内宿主与病原体的相互作用、细菌驱动的致癌感染。幽门螺杆菌 幽门螺杆菌感染是胃癌发生的头号危险因素。有趣的是，虽然 幽门螺杆菌定植非常普遍，只有一小部分感染者会继续发展 由于被殖民而导致的胃癌。然而，这相当于相当数量的胃癌。 病人。美国癌症协会目前提供的估计是，将有27,600个新病例 到2020年，确诊的胃癌患者中，估计有11,010人死于这种疾病。差异在于 宿主对感染的反应可以影响炎症和慢性氧化应激的水平 促进了胃癌的发生。这一建议是基于以下科学前提的：1.白介素1 17信号通路由于其“促炎”活性参与了炎症的驱动； 通过信号转导上皮细胞募集中性粒细胞并加强氧化，从而促进免疫病理 应激和2.IL-17受体信号也有助于限制胃粘膜内的慢性炎症 在幽门螺杆菌感染期间-这直接挑战了对IL-17途径的基本理解。在这 应用，我们提出了一种实验策略，将确定IL-17RA通过 IL-17RC调节幽门螺杆菌定植过程中的获得性免疫反应。我们假设幽门螺杆菌- 细胞特异性、TRAF依赖的IL-17调控介导的慢性炎症和癌变 发信号。此外，通过RA或RC的IL-17R信号对于促炎反应是必要的 在某些细胞类型(即上皮细胞)中，但在CD4+T细胞中发挥着被低估的抗炎作用 淋巴细胞活化。此外，我们提出了一种策略，将研究胃中的其他因素如何 微环境可能通过调节IL-17R信号复合体和肿瘤坏死因子影响IL-17信号转导 受体相关因子(TRAF)，它协调信号和随后的转录和增殖。 我们的研究方法将确定IL-17R的这些二分角色是否有助于宿主 控制幽门螺杆菌感染和炎症，不会发展成胃癌。该项目将提供 了解IL-17受体信号如何影响小鼠和小鼠的致癌过程 模型，以及在使用现有组织阵列的人体标本中。这些研究将有助于创建工具， 可用于未来的研究，以确定癌症进展的生物标记物，研究如何免疫- 治疗或疫苗可能会影响幽门螺杆菌定植的结果。最终，这些工具可以帮助 确定补充免疫疗法如何增强细菌清除，减少 提高抗菌素耐药性，降低患胃癌的风险。

Project Summary Helicobacter pylori infection can serve as a highly relevant, rigorous and tractable model to investigate an understudied area within the host-pathogen interactions, bacterial-driven carcinogenesis infection. Helicobacter pylori infection is the number one risk factor for the development of gastric cancer. Interestingly, while Helicobacter pylori colonization is very common, only a small percentage of infected people will go on to develop gastric cancer as a result of colonization. Nevertheless, this equates to a significant number of gastric cancer patients. Current estimates provided by the American Cancer Society, are that there will be 27,600 new cases of gastric cancer diagnosed and an estimated 11,010 deaths attributed to the disease in 2020. Differences in how a host responds to the infection can impact the level of inflammation and chronic oxidative stress which contribute to gastric carcinogenesis. This proposal is based on the following scientific premise: 1. The interleukin 17 signaling pathway has been implicated in driving inflammation due to its ‘pro-inflammatory’ activities; contributing to immunopathology through signaling epithelial cells to recruit neutrophils and potentiate oxidative stress and 2. IL-17 receptor signaling also contributes to limiting chronic inflammation within the gastric mucosa during H. pylori infection – which directly challenges the basic understanding of the IL-17 pathway. In this application, we propose an experimental strategy that will identify the cell-specific mechanisms by which IL-17RA and IL-17RC regulate the adaptive immune response during H. pylori colonization. We hypothesize that H. pylori- mediated chronic inflammation and carcinogenesis is controlled by cell-specific, TRAF-dependent IL-17 signaling. Further, that IL-17R signaling through either RA or RC is necessary for a pro-inflammatory response in some cell types (i.e. epithelial cells) but plays an underappreciated, anti-inflammatory role in CD4+ T lymphocyte activation. Further, we propose a strategy that will investigate how other factors in the gastric microenvironment might impact IL-17 signaling through modulating IL-17R signaling complexes and TNF receptor associated factors (TRAFs) which orchestrate signaling and subsequent transcription and proliferation. Our research approach will determine if these dichotomous roles of IL-17R contribute to the host’s ability to control H. pylori infection and inflammation without the development of gastric cancer. This project will provide an understanding of how IL-17 receptor signaling affects the development of carcinogenesis in both a mouse model, as well as in human specimens using an existing tissue array. These studies will help create tools which can be leveraged for future studies to identify biomarkers of cancer progression, investigate how immune- therapies or vaccines might affect outcomes of H. pylori colonization. Ultimately, these tools could help to determine how supplemental immunotherapies might enhance bacterial clearance, reduce development of antimicrobial resistance and reduce the risk of gastric cancer.