Control of intestinal microflora and inflammation by immune sensing of flagellin

了解宿主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。人类已经进化出两种类型的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，通过最小化给定数量的微生物造成的损害来限制宿主的健康成本。通常在我们的免疫学研究中，我们专注于宿主如何杀死病原体。相比之下，专注于耐受性的研究是有限的，因此耐受性的分子机制远未被很好地理解。该项目旨在利用宿主和肠道细菌之间的相互作用，特别是肠道和肠道植物群，作为一个模型系统，以确定新的耐受机制，可能适用于病原性感染。人体肠道内有数万亿的细菌，它们与粘膜免疫系统进行积极的对话。对于大多数宿主来说，这些相互作用的发生不会对健康产生不利影响。然而，这些机制的失调可能导致耐受性降低，从而导致严重的病理，如克罗恩病（CD）。强有力的证据表明，肠道细菌似乎是必不可少的CD的发展和细菌蛋白，鞭毛蛋白，已被发现是CD患者的优势抗原。因此，肠道和肠道植物群为发现新的耐受机制提供了令人兴奋的机会和理想的模型系统。本项目的目标是阐明先天免疫机制，介导鞭毛恶化的炎症性肠病使用体内小鼠模型的结肠炎，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，发现与野生型小鼠相比，先天免疫应答的两种鞭毛蛋白传感蛋白Naip 5和Ipaf的功能缺陷的小鼠突变体对结肠炎具有抗性。所提出的实验旨在检验Ipaf和/或Naip 5介导的对鞭毛蛋白的反应在炎症性肠病的发展和进展中是重要的这一假设。该项目的具体目标是：（1）确定Naip 5和Ipaf功能在炎症性肠病进展中的作用;（2）确定Naip 5和Ipaf在存在和不存在胃肠道损伤的情况下如何影响微生物群;（3）确定肠道微生物群落识别在Naip 5/Ipaf介导的胃肠道炎症恶化中的作用。拟议的实验将提供深入了解宿主如何能够耐受持续暴露于一种衍生于鸡胚的配体，并提供一种可能参与IBD进展的分子机制。

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.