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.

项目概要 幽门螺杆菌感染可以作为高度相关、严格且易于处理的模型来研究幽门螺杆菌感染 宿主与病原体相互作用、细菌驱动的致癌感染等领域的研究不足。 幽门螺杆菌感染是胃癌发生的第一大危险因素。 幽门螺杆菌定植非常常见，只有一小部分感染者会继续发展 然而，这相当于相当数量的胃癌。 美国癌症协会目前估计将有 27,600 例新病例。 2020 年诊断出的胃癌人数和估计有 11,010 人死于该疾病。 宿主对感染的反应会影响炎症和慢性氧化应激的水平，从而影响炎症和慢性氧化应激的水平。 这一建议基于以下科学前提： 1.白细胞介素。 由于其“促炎症”活性，17 信号通路与炎症驱动有关； 通过向上皮细胞发出信号来募集中性粒细胞并增强氧化，从而促进免疫病理学 2. IL-17 受体信号传导也有助于限制胃粘膜内的慢性炎症 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。 应用中，我们提出了一种实验策略，该策略将确定 IL-17RA 的细胞特异性机制 IL-17RC 调节幽门螺杆菌定植期间的适应性免疫反应。 介导的慢性炎症和癌变由细胞特异性、TRAF 依赖性 IL-17 控制 此外，通过 RA 或 RC 的 IL-17R 信号传导对于促炎症反应是必需的 存在于某些细胞类型（即上皮细胞）中，但在 CD4+ T 中发挥着未被充分认识的抗炎作用 此外，我们提出了一种策略来研究胃中其他因素的作用。 微环境可能通过调节 IL-17R 信号复合物和 TNF 影响 IL-17 信号传导 受体相关因子（TRAF）协调信号传导以及随后的转录和增殖。 我们的研究方法将确定 IL-17R 的这些二分作用是否有助于宿主的能力 该项目将提供控制幽门螺杆菌感染和炎症而不发展为胃癌的机会。 了解 IL-17 受体信号传导如何影响小鼠的癌变发展 模型以及使用现有组织阵列的人体样本，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志物，研究免疫如何 疗法或疫苗可能会影响幽门螺杆菌定植的结果，最终，这些工具可能有助于 确定补充免疫疗法如何增强细菌清除，减少细菌的发展 抗菌药物耐药性并降低胃癌风险。

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。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Horvath Jr, Dennis J;Radin, Jana N;Cho, Sung Hoon;Washington, M Kay;Algood, Holly M Scott
• 通讯作者: Algood, Holly M Scott

Purine Biosynthesis Metabolically Constrains Intracellular Survival of Uropathogenic Escherichia coli.

嘌呤生物合成在代谢上限制泌尿道致病性大肠杆菌的细胞内存活。

• 发表时间: 2017-01
• 影响因子: 3.1
• 作者: Shaffer, Carrie L;Zhang, Ellisa W;Dudley, Anne G;Dixon, Beverly R E A;Guckes, Kirsten R;Breland, Erin J;Floyd, Kyle A;Casella, Daniel P;Algood, Holly M Scott;Clayton, Douglass B;Hadjifrangiskou, Maria
• 通讯作者: Hadjifrangiskou, Maria

Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation.

幽门螺杆菌通过脂质 A 修饰和相关生物膜形成来抵抗钙卫蛋白的抗菌活性。

• 发表时间: 2015-12-08
• 影响因子: 6.4
• 作者: Gaddy, Jennifer A;Radin, Jana N;Cullen, Thomas W;Chazin, Walter J;Skaar, Eric P;Trent, M Stephen;Algood, Holly M S
• 通讯作者: Algood, Holly M S

IL-23 Contributes to Control of Chronic Helicobacter Pylori Infection and the Development of T Helper Responses in a Mouse Model.

IL-23 有助于控制慢性幽门螺杆菌感染和小鼠模型中 T 辅助细胞反应的发展。

• 发表时间: 2012
• 作者: Horvath DJ Jr;Washington MK;Cope VA;Algood HM
• 通讯作者: Algood HM