Mechanisms of Protection by Commensal Fungi in Colitis

描述（由申请人提供）：哺乳动物肠道中有一个不同的共生细菌群落。共生菌群与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。尽管有一些研究报道了人类和小鼠粪便中存在真菌DNA，但肠道真菌在很大程度上被忽视了，它们与肠道免疫系统的相互作用也没有得到研究。我们最近报道了丰富且高度多样化的真菌物种（肠道真菌组）是小鼠肠道微生物群的重要组成部分。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，这是对本地真菌的反应改变的结果。然而，并非所有的真菌都是“坏的”。我们发现，在DSS诱导的结肠炎模型中，小鼠共生菌株纤维酵母菌（S. fibuligera ID1）对肠道炎症具有保护作用。人们早就知道，某些种类的共生菌可以调节粘膜免疫反应，控制Th1、Th2、Th17和Treg细胞之间的平衡，并被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。本研究旨在通过研究肠道真菌与细菌、肠上皮以及肠道先天免疫系统和适应性免疫系统的相互作用，来定义肠道真菌的保护性及其保护机制。我们假设共生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。在特异性目标1中，我们将使用DSS诱导结肠炎的小鼠模型来评估共生真菌和相关真菌的保护特性。在Specific Aim 2中，我们将扩展分析，以观察纤维链球菌ID1和其他真菌在针对不同类型结肠炎病因的模型中的保护作用，包括T细胞介导和感染性微生物介导的疾病。在特异性目标3中，我们将探索保护机制，包括真菌诱导的细菌微生物组改变，肠道真菌与肠上皮和先天免疫系统的相互作用，以及肠内T细胞偏倚的调节。

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.