Control of intestinal microflora and inflammation by immune sensing of flagellin

了解宿主用来防御感染和降低疾病严重性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降至最低，从而限制宿主的健康成本。通常在我们的免疫学研究中，我们关注的是宿主如何杀死病原体。相比之下，关注耐受性的研究是有限的，因此对耐受性的分子机制了解得远远不够。该项目旨在利用宿主和共生细菌之间的相互作用，特别是肠道和共生菌群，作为一个模型系统来确定可能应用于病原性感染的新的耐受机制。人体肠道中含有数以万亿计的细菌，这些细菌与粘膜免疫系统进行积极对话。对于大多数宿主来说，这些相互作用的发生不会对健康造成不利影响。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，共生细菌似乎对CD的发展是必不可少的，细菌蛋白鞭毛蛋白已被发现是CD患者的主要抗原。因此，肠道和共生菌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。本项目的目标是利用活体小鼠结肠炎模型、小鼠遗传学和常规免疫学和微生物学技术，阐明介导鞭毛蛋白加重炎症性肠病的先天免疫机制。在初步实验中，与野生型小鼠相比，缺乏两种天然免疫反应鞭毛感应蛋白功能的小鼠突变体NAip5和IPAF被发现对结肠炎具有抵抗力。拟议的实验旨在验证IPAF和/或NAIP5介导的对鞭毛蛋白的反应在炎症性肠病的发生和发展中起重要作用的假设。该项目的具体目标是：(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如何影响微生物区系；以及(3)确定共生微生物区系识别在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共生衍生配体的持续暴露，并提供可能参与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.