Mechanisms of Protection by Commensal Fungi in Colitis

描述（由申请人提供）：哺乳动物肠道中定植有多种肠道细菌。肠道微生物区系和肠道免疫系统之间的相互作用对于在免疫宿主防御机制和组织健康之间建立适当的平衡至关重要。虽然一些研究报告了人类和小鼠粪便中真菌DNA的存在，但肠道真菌在很大程度上被忽视，它们与肠道免疫系统的相互作用尚未研究。我们最近报道了一个丰富的和高度多样化的真菌物种（肠道菌群）的人口是一个重要组成部分的小鼠肠道菌群。我们发现肠道真菌通过先天免疫受体Dectin-1与免疫系统相互作用，缺乏Dectin-1的小鼠对化学诱导的结肠炎的易感性增加，这是对本土真菌反应改变的结果。然而，并非所有的真菌都是“坏”的。我们发现一种扣囊拟复膜线虫（S. fibuligera）的小鼠寄生株。fibuligera ID 1）在DSS诱导的结肠炎模型中对肠道炎症具有保护作用。长期以来，已知某些种类的肠道细菌调节粘膜免疫应答，决定Th 1、Th 2、Th 17和Treg细胞之间的平衡，并已广泛用于预防和治疗肠道疾病。只有少数研究报告真菌可以具有类似的保护特性，尽管这种“保护”背后的机制在很大程度上是未知的。该提案的重点是通过研究它们与细菌和肠上皮以及肠道中的先天性和适应性免疫系统的相互作用来定义保护性肠道真菌及其保护机制。我们推测，真菌与肠道细菌和粘膜免疫系统相互作用，诱导耐受性机制，导致肠道炎症和结肠炎的抑制。我们将在三个具体目标中检验我们的假设。在具体目标1中，我们将使用DSS诱导的结肠炎的小鼠模型来评估真菌和相关真菌的保护特性。在具体目标2中，我们将扩展分析，看看S的保护。fibuligera ID 1和其他真菌在靶向结肠炎病因学的不同分支的模型中，包括T细胞介导的和感染性微生物介导的疾病。在具体目标3中，我们将探索保护机制，包括细菌微生物组中真菌诱导的改变，肠道真菌与肠上皮和先天免疫系统的相互作用，以及肠道中T细胞偏好的调节。

DESCRIPTION (provided by applicant): A diverse community of commensal bacteria colonizes the mammalian gut. Interactions between the commensal microflora and the gut immune system are critical for establishing a proper balance between immune host defense mechanisms and tissue health. Although a few studies have reported the presence of fungal DNA in human and murine feces, gut fungi have been largely overlooked and their interactions with the gut immune system have not been investigated. We have recently reported an abundant and highly diverse population of fungal species (gut mycobiome) to be a significant component of the murine intestinal microbiota. We found that gut fungi interact with the immune system through the innate immune receptor Dectin-1 and that mice lacking Dectin-1 exhibit increased susceptibility to chemically-induced colitis, which is a result of altered responses to indigenous fungi. However not all fungi are "bad". We found that a mouse commensal strain of Saccharomycopsis fibuligera (S. fibuligera ID1) was protective against intestinal inflammation in a DSS- induced model of colitis. Certain species of commensal bacteria have long been known to modulate mucosal immune responses, dictate the balance between Th1, Th2, Th17 and Treg cells and have been widely used for prevention and treatment of intestinal disorders. Only a few studies have reported that fungi can have similar protective properties, although the mechanism behind such "protection" is largely unknown. This proposal focuses on defining protective gut fungi and their mechanisms of protection by studying their interaction with bacteria and the intestinal epithelium as well as with the innate and adaptive immune systems in the gut. We hypothesize that commensal fungi interact with gut bacteria and with the mucosal immune system to induce tolerogenic mechanisms, leading to suppression of intestinal inflammation and colitis. We will test our hypothesis in three specific aims. In Specific Aim 1 we will evaluate commensal and related fungi for protective properties using a mouse model of DSS induced colitis. In Specific Aim 2 we will extend the analysis to look at protection by S. fibuligera ID1 ad other fungi in models targeting different arms of colitis etiology including T cell-mediated and infectious microbe-mediated disease. In Specific Aim 3 we will explore mechanisms of protection including fungal-induced alterations in the bacterial microbiome, interaction of gut fungi with the intestinal epithelium and the innate immune system, and regulation of T cell bias in the intestine.