Control of intestinal microflora and inflammation by immune sensing of flagellin

描述（由申请人提供）：了解宿主用来防御感染和降低疾病严重程度的策略是免疫学和宿主-微生物相互作用研究的最终目标之一。宿主已经进化出两种防御策略来限制感染对健康的影响。首先，宿主可以利用抗性机制直接攻击病原体以阻止入侵或消除感染。第二种策略包括耐受机制，通过将给定数量的微生物造成的损害最小化来限制宿主的健康成本。通常在我们的免疫学研究中，我们关注宿主如何杀死病原体。相比之下，对耐受性的研究是有限的，因此对耐受性的分子机制知之甚少。该项目旨在利用宿主与共生菌之间的相互作用，特别是肠道和共生菌群之间的相互作用，作为一个模型系统，以确定可能应用于致病性感染的新型耐受性机制。人体肠道中有数万亿细菌，它们与粘膜免疫系统进行着积极的对话。对大多数宿主来说，这些相互作用对健康没有不利影响。然而，这些机制的失调可能导致耐受性降低，导致严重的病理，如克罗恩病（CD）。强有力的证据表明，共生菌似乎对乳糜泻的发展至关重要，而细菌蛋白鞭毛蛋白已被发现是乳糜泻患者的显性抗原。因此，肠道和共生菌群为发现新的耐受性机制提供了一个令人兴奋的机会和理想的模型系统。该项目的目的是阐明先天免疫机制，介导鞭毛蛋白加剧炎症性肠病使用体内小鼠结肠炎模型，小鼠遗传学和传统的免疫学和微生物学技术。在初步实验中，与野生型小鼠相比，缺乏先天免疫反应中两种鞭毛蛋白传感蛋白Naip5和Ipaf功能的小鼠突变体对结肠炎具有抗性。本实验旨在验证Ipaf-和/或naip5介导的鞭毛蛋白反应在炎症性肠病的发生和进展中很重要的假设。该项目的具体目的是：(1)确定Naip5和Ipaf功能在炎症性肠病进展中的作用；(2)确定在存在和不存在胃肠道损伤的情况下，Naip5和Ipaf如何影响微生物群；(3)确定共生菌群识别在Naip5/ ipaf介导的胃肠道炎症加重中的作用。拟议的实验将深入了解宿主如何耐受持续暴露于共体衍生的配体，并提供可能参与IBD进展的分子机制。

DESCRIPTION (provided by applicant): Understanding the strategies utilized by a host to defend against infections and reduce disease severity is one of the ultimate goals of immunology and studies of host-microbe interactions. Hosts have evolved two types of defense strategies to limit the impact of infection on health. First, hosts can use resistance mechanisms to directly attack a pathogen to block invasion or eliminate the infection. The second strategy includes tolerance mechanisms that work to limit the health costs to a host by minimizing the amount of damage caused by a given number of microbes. Typically in our immunological studies, we focus on how a host kills pathogens. By contrast, studies that focus on tolerance are limited and therefore the molecular mechanisms of tolerance are far less well understood. This project is designed to utilize the interactions between a host and commensal bacteria, specifically the intestine and the commensal flora, as a model system to identify novel tolerance mechanisms that may be applied to pathogenic infections. The human intestine harbors trillions of bacteria that are involved in an active dialogue with the mucosal immune system. For the majority of hosts, these interactions occur with no adverse effects on health. However, dysregulation of these mechanisms may cause a reduction of tolerance leading to severe pathologies such as Crohn's disease (CD). Strong evidence suggests that the commensal bacteria appear to be essential for the development of CD and the bacterial protein, flagellin, has been found to be a dominant antigen in CD patients. Therefore, the intestine and the commensal flora provide an exciting opportunity and ideal model system to discover novel tolerance mechanisms. The goal of this project is to elucidate an innate immune mechanism that mediates flagellin-exacerbation of inflammatory bowel disease using an in vivo mouse model of colitis, mouse genetics and conventional immunological and microbiological techniques. In preliminary experiments, mouse mutants deficient for the function of two flagellin-sensing proteins of the innate immune response, Naip5 and Ipaf, were found to be resistant to colitis compared to wild type mice. The proposed experiments are designed to test the hypothesis that Ipaf- and/or Naip5-mediated responses to flagellin are important in the development and progression of inflammatory bowel disease. The specific aims of the project are: (1) Determine the role of Naip5 and Ipaf function in the progression of inflammatory bowel disease; (2) Determine how Naip5 and Ipaf affect the microbiota in the presence and absence of gastrointestinal insult; and, (3) Determine the role of commensal microflora recognition in Naip5/Ipaf-mediated exacerbation of gastrointestinal inflammation. The proposed experiments will provide insight into how hosts can tolerate constant exposure to a commensal-derived ligand and provide a molecular mechanism that may be involved in the progression of IBD. PUBLIC HEALTH RELEVANCE: This project is relevant to human health because understanding the flagellin sensing pathways that contribute to the onset and progression of gastrointestinal inflammation will be important for developing therapeutics for CD. Additionally, understanding how a host can tolerate the commensal flora provides an excellent opportunity to reveal novel molecular mechanisms of tolerance that could be applicable to pathogenic infections and potential targets for drug therapy. Furthermore, because tolerance mechanisms are predicted to have a neutral or positive effect on microbial fitness, microbes are not predicted to evolve antagonistic traits to counteract tolerance strategies and therefore should not develop resistance to drugs that enhance tolerance.