Chemokines in host defense to Campylobacter jejuni

描述（由申请人提供）：本R21研究计划是响应“生物防御和新兴传染病研究机会”，no - ai -02-023提交的，有两个特定目的，旨在增加我们对空肠弯曲杆菌小肠结肠炎发病机制的理解。肠上皮包括一个动态的物理屏障，它维持先天宿主防御反应的活跃库，以限制临床上重要的食物和水传播病原体的进入。这些机制包括调节趋化因子的产生，以协调适当的先天和适应性免疫效应反应。空肠梭菌是世界上引起细菌性腹泻的主要原因。然而，尽管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空肠梭菌小肠结肠炎发病机制的新信息，并将作为重要的第一步，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。Aim 1的研究将验证空肠梭菌感染人肠上皮细胞刺激中性粒细胞、树突状细胞和T淋巴细胞趋化因子产生的假设，我们假设效应细胞协同作用，限制空肠梭菌进入体内。培养模型肠上皮被空肠梭菌感染，并评估调节上皮趋化因子产生的信号机制。为了确定细菌的致病性，Aim 2的研究将利用空肠弯曲杆菌突变体来验证特异性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。诱导上皮趋化因子的表达将在空肠梭菌鞭毛突变体中进行测试，以及从基于启动子陷阱的方法中选择的候选突变体来定义新的毒力因子。总之，这些研究将为细胞信号机制和细菌基因产物调控肠上皮趋化因子的产生作为空肠梭菌的核心宿主防御功能提供新的见解。了解肠上皮宿主防御人类空肠梭菌感染的细胞和生化机制，是制定预防治疗策略以调节宿主-病原体相互作用以有利于宿主的核心。

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.