Chemokines in host defense to Campylobacter jejuni

趋化因子在宿主空肠弯曲杆菌防御中的作用

• 批准号: 6803523
• 负责人: Michael B Dwinell
• 金额: $ 30万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803523
• 关键词: Campylobacter; bacterial cytopathogenic effect; bactericidal immunity; biological signal transduction; chemoattractants; chemokine; colitis; enzyme linked immunosorbent assay; gastrointestinal epithelium; gene targeting; host organism interaction; interferon gamma; microorganism culture; mucosal immunity; mutant; nuclear factor kappa beta; polymerase chain reaction; tissue /cell culture; virulence

DESCRIPTION (provided by applicant): This R21 research proposal, submitted in response to "Biodefense and Emerging Infectious Diseases Research Opportunities", NOT-AI-02-023, has two specific aims designed to increase our understanding of the pathogenesis of Campylobacter jejuni enterocolitis. The intestinal epithelium comprises a dynamic physical barrier that maintains an active repertoire of innate host defense responses to limit entry of clinically significant food- and water-borne pathogens. These mechanisms include the regulated production of chemokines to coordinate the appropriate innate and adaptive immune effector response. C. jejuni is a leading cause of bacterial diarrheal disease in the world. However, while relatively little is known of the pathophysiologic mechanisms employed to infect the human intestinal tract and elicit disease, interaction at the intestinal epithelium is the most common pathogenic feature of infection. The overall objective of this research proposal is to obtain novel information on the mechanisms of pathogenesis to C. jejuni enterocolitis and will, as an important first step, focus on the coordinated production of chemokines by the cells of the intestinal epithelium as a significant host defense mechanism. Studies in Aim 1 will test the hypothesis that C. jejuni infection of human intestinal epithelial cells stimulates production of chemokines for neutrophils, dendritic cells and T lymphocytes, effectors cells that we postulate act in concert to limit C. jejuni entry in vivo. A culture model intestinal epithelium will be infected with C. jejuni and the signaling mechanisms regulating epithelial chemokine production assessed. To define bacterial pathogenicity, studies in Aim 2 will utilize C. jejuni mutants to test the hypothesis that specific Campylobacter virulence factors induce host epithelial cell chemokine expression. Induction of epithelial chemokine expression will be tested in C. jejuni flagella mutants, as well as mutants selected from candidates revealed from a promoter trap-based approach to define novel virulence factors. Together, these studies will provide new insights into the cellular signaling mechanisms and bacterial gene products regulating intestinal epithelial chemokine production as a central host defense function to C. jejuni. Understanding the cellular and biochemical mechanisms of intestinal epithelial host defense to human C. jejuni infection are central to the development of preventative therapeutic strategies to modulate host-pathogen interactions to favor the host.

描述（由申请人提供）：这项 R21 研究提案是针对“生物防御和新兴传染病研究机会”NOT-AI-02-023 提交的，有两个具体目标，旨在增进我们对空肠弯曲菌小肠结肠炎发病机制的了解。 肠上皮包含动态物理屏障，维持先天宿主防御反应的活性，以限制临床上重要的食源性和水源性病原体的进入。 这些机制包括调节趋化因子的产生，以协调适当的先天性和适应性免疫效应反应。 空肠弯曲菌是世界上细菌性腹泻病的主要原因。 然而，虽然人们对感染人类肠道并引发疾病的病理生理机制知之甚少，但肠上皮的相互作用是感染最常见的致病特征。 本研究计划的总体目标是获得有关空肠弯曲菌小肠结肠炎发病机制的新信息，并且作为重要的第一步，重点关注肠上皮细胞协调产生趋化因子作为重要的宿主防御机制。 目标 1 中的研究将检验以下假设：空肠弯曲菌感染人肠上皮细胞会刺激中性粒细胞、树突状细胞和 T 淋巴细胞产生趋化因子，我们假设这些效应细胞协同作用以限制空肠弯曲菌进入体内。 培养模型肠上皮将被空肠弯曲菌感染，并评估调节上皮趋化因子产生的信号机制。 为了定义细菌致病性，目标 2 中的研究将利用空肠弯曲菌突变体来检验特定弯曲杆菌毒力因子诱导宿主上皮细胞趋化因子表达的假设。 将在空肠弯曲菌鞭毛突变体以及从基于启动子陷阱的方法揭示的候选突变体中测试上皮趋化因子表达的诱导，以定义新的毒力因子。 总之，这些研究将为调节肠上皮趋化因子产生作为空肠弯曲菌的核心宿主防御功能的细胞信号传导机制和细菌基因产物提供新的见解。 了解肠上皮宿主防御人类空肠弯曲菌感染的细胞和生化机制对于制定预防性治疗策略以调节宿主与病原体的相互作用以有利于宿主至关重要。