Host immunity to commensal gut fungi

描述（由申请人提供）：许多研究已经记录了特定肠道细菌在调节粘膜免疫和指导组织发育和修复中发挥的重要作用，但我们对肠道真菌如何与免疫系统相互作用或促进肠道炎症性疾病知之甚少。对肠道微生物进行分类的研究通常集中在细菌上，术语“肠道细菌”和“肠道微生物组”经常互换使用。更好地了解肠道真菌在健康和疾病中的作用有两个障碍，一是对肠道真菌的数量和类型有一个很好的认识，二是有一个模型，在这个模型中，对肠道真菌的免疫反应可以被操纵。我的实验室一直在研究？-葡聚糖受体Dectin-1在宿主防御中的作用Dectin-1在巨噬细胞和树突状细胞上表达，对防御真菌至关重要。Dectin-1通过一种叫做CARD9的细胞内信号接头分子发出炎症反应信号，CARD9是一种蛋白质，其特定的遗传变异与溃疡性结肠炎和克罗恩病密切相关。我们观察到缺乏Dectin-1的小鼠比野生型小鼠更容易患DSS诱导的急性结肠炎，这种增强的敏感性是由于肠道真菌。我们已经开始通过高通量多标签焦磷酸测序来表征肠道真菌菌群，并已鉴定出数百种肠道真菌。因此，我们正在开发一种肠道真菌数量和类型的感觉，以及一种可以操纵肠道真菌免疫反应的模型。我们的总体假设是？-葡聚糖受体Dectin-1负责调查真菌的肠道菌群，并协调宿主免疫反应，形成微生物群并导致肠道炎症。我们将从四个方面探讨这一假设。在

DESCRIPTION (provided by applicant): Many studies have documented the essential role that specific intestinal bacteria play in tuning mucosal immunity and in instructing tissue development and repair, but we know very little about how intestinal fungi interact with the immune system or contribute to intestinal inflammatory diseases. Studies cataloging intestinal microbes have typically focused on the bacteria, and the terms "intestinal bacteria" and "intestinal microbiome" are often used interchangeably. Two barriers to developing a better understanding of the role of gut fungi in health and disease are having a good sense of the numbers and types of fungi in the gut and having a model in which immune responses to gut fungi can be manipulated. My laboratory has been studying the role of the ?-glucan receptor Dectin-1 in host defense. Dectin-1 is expressed on macrophages and dendritic cells and is essential for defense against fungi. Dectin-1 signals inflammatory responses through an intracellular signaling adaptor molecule called CARD9, a protein for which specific genetic variants are strongly associated with ulcerative colitis and Crohn's disease. We have observed that mice lacking Dectin-1 are more susceptible to acute colitis induced by DSS than wild type mice and that this enhanced sensitivity is due to intestinal fungi. We have begun to characterize the intestinal fungal microflora by high throughput multitag pyrosequencing and have identified several hundred intestinal fungi. Thus, we are developing a sense of the numbers and types of fungi in the gut and a model in which immune responses to gut fungi can be manipulated. Our overall hypothesis is that the ?-glucan receptor Dectin-1 is responsible for surveying the gut microflora for fungi and orchestrating a host immune response that shapes the microflora and contributes to intestinal inflammatory conditions. We will explore this hypothesis in four aims. In aim 1 we will characterize the fungal microbiome in wild type, Dectin-1-/-, and CARD9-/- mice in resting and inflamed conditions. In aim 2 we will define the role of Decitn-1 in sampling intestina fungi and the role of intestinal fungi in driving inflammatory responses. In aim 3 we will determine whether mice lacking CARD9 exhibit the same fungal-driven intestinal inflammation as observed in Dectin-1 knockout mice. In aim 4 we will determine whether Dectin-1 and CARD9 knockout mice also exhibit enhanced susceptibility to spontaneous disease and disease induced by T cell transfer.