Chemokines in host defense to Campylobacter jejuni

描述（由申请人提供）：该R21研究提案是为了响应“生物防御和新兴传染病研究机会”（NOT-AI-02-023）而提交的，有两个具体目标，旨在增加我们对空肠弯曲菌小肠结肠炎发病机制的理解。 肠上皮包括动态的物理屏障，其维持先天宿主防御反应的活性库以限制临床上显著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子应答。 C.空肠是世界上细菌性结肠炎的主要病因。 然而，虽然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的最常见致病特征。 这项研究的总体目标是获得新的信息的发病机制，以C。空肠小肠结肠炎，并将作为重要的第一步，集中在协调生产的趋化因子的细胞的肠上皮细胞作为一个重要的主机防御机制。 目标1中的研究将检验C.空肠感染的人肠上皮细胞刺激中性粒细胞、树突状细胞和T淋巴细胞的趋化因子的产生，我们假设这些效应细胞协同作用以限制C.空肠进入体内。 培养模型肠上皮将被C.空肠和调节上皮细胞趋化因子产生的信号传导机制进行评估。 为了确定细菌的致病性，目标2中的研究将利用C.空肠弯曲菌突变体，以检验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。 上皮趋化因子表达的诱导将在C.空肠鞭毛突变体，以及从基于启动子陷阱的方法揭示的候选物中选择的突变体，以定义新的毒力因子。 总之，这些研究将为细胞信号机制和细菌基因产物调节肠上皮细胞趋化因子的产生提供新的见解，作为宿主对C.空肠。 了解肠上皮宿主防御人类念珠菌的细胞和生化机制。空肠感染是发展调节宿主-病原体相互作用以有利于宿主的预防性治疗策略的核心。

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.