The role of T cell derived cytokines in Helicobacter pylori

T细胞源性细胞因子在幽门螺杆菌中的作用

• 批准号: 10554253
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554253
• 关键词: Acute; Adaptor Signaling Protein; Address; Affect; American Cancer Society; Animal Model; Anti-Inflammatory Agents; Antibodies; Antimicrobial Resistance; Area; Automobile Driving; B-Lymphocytes; Bacteria; Bacterial Infections; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cancer Patient; Cells; Cessation of life; Chronic; Complex; Data; Development; Diet; Disease; Environmental Risk Factor; Epithelial Cells; Equation; Equilibrium; Exhibits; Feedback; Fibroblasts; Future; Gastric Tissue; Gastric mucosa; Gastritis; Gene Targeting; Genetic Transcription; Goals; Helicobacter Infections; Helicobacter Pylori-Related Malignant Neoplasm; Helicobacter pylori; Histologic; Human; IL17 gene; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Indolent; Infection; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Lesion; Location; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Mediating; Modeling; Molecular Biology Techniques; Mus; Mutant Strains Mice; Neutrophil Infiltration; Outcome; Oxidative Stress; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peptic Ulcer; Persons; Play; Production; Proliferating; Receptor Signaling; Regulation; Research; Risk; Risk Factors; Risk Reduction; Role; Signal Pathway; Signal Transduction; Smoking; Specimen; Stomach; Stromal Cells; T cell differentiation; T-Lymphocyte; TNF Receptor-Associated Factors; TRAF4 gene; Testing; Tissue Microarray; Tissues; Transgenic Mice; Vaccines; Virulence Factors; Wild Type Mouse; adaptive immune response; antimicrobial; biobank; biomarker development; biomarker identification; cancer diagnosis; carcinogenesis; cell type; chemokine; chronic infection; cytokine; design; gastric carcinogenesis; gastrointestinal epithelium; human tissue; immunopathology; interleukin-21; malignant stomach neoplasm; microbial; mouse model; neutrophil; pathogen; pathogenic bacteria; pathogenic fungus; potential biomarker; premalignant; progression marker; receptor; recruit; response; tool; tool development; translational impact; tumor progression; ubiquitin isopeptidase

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.

项目摘要 幽门螺杆菌感染可以作为一个高度相关的，严格的和易处理的模型，以调查 宿主-病原体相互作用、细菌驱动的致癌感染等研究不足的领域。螺杆 幽门螺杆菌感染是导致胃癌的头号危险因素。有趣的是， 幽门螺杆菌定植是很常见的，只有一小部分感染者会继续发展 胃癌是由细菌定植引起的。然而，这相当于相当数量的胃癌 患者美国癌症协会目前的估计是，将有27，600个新病例 在2020年，诊断出胃癌的人数约为11，010人，估计有11，010人死于该疾病。差异 宿主对感染的反应会影响炎症和慢性氧化应激的水平， 有助于胃癌的发生。这一建议基于以下科学前提：1。白细胞介素 17信号通路由于其“促炎”活性而与驱动炎症有关; 通过向上皮细胞发出信号以募集嗜中性粒细胞并增强氧化应激， 压力和2。IL-17受体信号传导也有助于限制胃粘膜内的慢性炎症 在H.幽门螺杆菌感染-这直接挑战了对IL-17途径的基本理解。在这 应用，我们提出了一个实验策略，将确定细胞特异性机制，IL-17 RA 和IL-17 RC调节H.幽门定植。我们假设H.幽门- 介导的慢性炎症和癌变受细胞特异性TRAF依赖性IL-17控制 信号此外，通过RA或RC的IL-17 R信号传导对于促炎反应是必需的 在某些细胞类型（即上皮细胞）中，但在CD 4 + T细胞中起着未被充分认识的抗炎作用 淋巴细胞活化此外，我们提出了一种策略，将调查如何在胃的其他因素， 微环境可能通过调节IL-17 R信号复合物和TNF-α来影响IL-17信号传导 受体相关因子（TRAF），其协调信号传导和随后的转录和增殖。 我们的研究方法将确定IL-17 R的这些二分作用是否有助于宿主的能力， 对照H.幽门螺杆菌感染和炎症而不发展为胃癌。本项目将提供 了解IL-17受体信号传导如何影响小鼠和 模型，以及使用现有的组织阵列在人体标本中。这些研究将有助于创造工具， 可以用于未来的研究，以确定癌症进展的生物标志物，研究免疫- 治疗或疫苗可能会影响H.幽门定植。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 抗微生物药物耐药性和降低胃癌的风险。

项目成果

The interleukin-17 receptor B subunit is essential for the Th2 response to Helicobacter pylori, but not for control of bacterial burden.

白细胞介素 17 受体 B 亚基对于 Th2 对幽门螺杆菌的反应至关重要，但对于控制细菌负荷却不是必需的。

• DOI: 10.1371/journal.pone.0060363
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: HorvathJr,DennisJ;Radin,JanaN;Cho,SungHoon;Washington,MKay;Algood,HollyMScott
• 通讯作者: Algood,HollyMScott