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: 6675486
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675486
• 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“生物反应和新兴的传染病研究机会”而提交的，而不是AI-02-023，其两个具体目的旨在增加我们对弯曲杆菌的发病机制的理解。 肠上皮包括动态的物理屏障，该障碍物保持了天生的宿主防御反应的积极曲目，以限制临床上重要的食物和水传播病原体的进入。 这些机制包括趋化因子的调节产生，以协调适当的先天和适应性免疫效应子反应。 空肠C.是世界上细菌性腹泻病的主要原因。 然而，尽管对感染人类肠道和引起疾病的病理生理机制的了解相对较少，但肠上皮的相互作用是感染的最常见致病特征。 该研究建议的总体目的是获取有关空肠梭菌炎发病机理机制的新信息，并将其作为重要的第一步，将重点放在肠上皮细胞协调的趋化因子上，作为重要的宿主防御机制。 AIM 1中的研究将检验以下假说：人类肠上皮细胞的空肠梭菌感染刺激了中性粒细胞，树突状细胞和T淋巴细胞的趋化因子的产生，我们假设我们协同作用的作用细胞，以限制Vivo中的jejuni进入。 培养模型的肠道上皮将被空肠梭菌感染，并评估了调节上皮趋化因子产生的信号传导机制。 为了定义细菌的致病性，AIM 2中的研究将利用Jejuni突变体来检验以下假设：特定的弯曲杆菌毒力诱导宿主上皮细胞趋化因子表达。 将在Jejuni鞭毛突变体中测试上皮趋化因子表达，以及从基于启动子陷阱的方法中揭示的候选者中选择的突变体，以定义新的毒力因子。 总之，这些研究将提供有关细胞信号传导机制和细菌基因产物的新见解，以调节肠上皮趋化因子的产生，这是jejuni的中心宿主防御功能。 了解肠上皮宿主防御对人梭菌感染的细胞和生化机制对于开发预防性治疗策略以调节宿主 - 病原体相互作用以偏爱宿主是至关重要的。