Host immunity to commensal gut fungi

宿主对共生肠道真菌的免疫力

• 批准号: 8340682
• 负责人: David M. Underhill
• 金额: $ 45.18万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340682
• 关键词: Acute; Antibodies; Antifungal Agents; Antigens; Appearance; Automobile Driving; Bacteria; Biomass; Cataloging; Catalogs; Cells; Chronic; Colitis; Communities; Crohn' s disease; Data; Dendritic Cells; Development; Disease; Disease model; Exhibits; Feces; Genes; Genetic Variation; Glucans; Growth; Health; Host Defense; Human; Immune response; Immune system; Immunity; Immunologic Surveillance; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestinal Mucosa; Intestines; Knockout Mice; Laboratories; Lamina Propria; Mediating; Microbe; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Ovalbumin; Pathology; Play; Predisposition; Proteins; Recombinant DNA; Rest; Role; Sampling; Severities; Shapes; Signal Transduction; Surveys; T cell response; T-Lymphocyte; Tissues; Toll-like receptors; Ulcerative Colitis; Wild Type Mouse; Yeasts; adaptive immunity; commensal microbes; dectin 1; fungus; genetic variant; gut microflora; human disease; intestinal epithelium; macrophage; mathematical ability; microbiome; receptor; repaired; response

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. PUBLIC HEALTH RELEVANCE: The intestines are full of microbes, and the numbers and kinds of microbes found there can be a significant factor in intestinal chronic inflammatory disease such as Inflammatory Bowel Disease. While many studies have focused on how intestinal bacteria are detected by the immune system, little is known about how intestinal fungi are detected. This study aims to define the repertoire of fungi found in mouse intestines and use mice lacking specific genes to understand how the immune system interacts with intestinal 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导致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，并且术语“肠道细菌”和“肠道微生物组”经常互换使用。更好地理解肠道真菌在健康和疾病中的作用的两个障碍是对肠道中真菌的数量和类型有很好的了解，并有一个模型可以操纵对肠道真菌的免疫反应。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，对于防御真菌至关重要。Dectin-1通过称为CARD 9的细胞内信号转导衔接分子发出炎症反应信号，CARD 9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。我们已经观察到，缺乏Dectin-1的小鼠比野生型小鼠更容易受到DSS诱导的急性结肠炎的影响，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，并且已经鉴定了数百种肠道真菌。因此，我们正在开发一种对肠道真菌数量和类型的认识，以及一种可以操纵对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负责调查肠道微生物菌群中的真菌，并协调宿主免疫反应，该免疫反应形成微生物菌群并促成肠道炎症状况。我们将从四个方面探讨这一假设。在 目的1我们将表征处于静息和发炎条件下的野生型、Dectin-1-/-和CARD 9-/-小鼠中的真菌微生物组。在目标2中，我们将定义Decitn-1在采样肠道真菌中的作用以及肠道真菌在驱动炎症反应中的作用。在目标3中，我们将确定缺乏CARD 9的小鼠是否表现出与在Dectin-1敲除小鼠中观察到的相同的真菌驱动的肠道炎症。在目标4中，我们将确定Dectin-1和CARD 9敲除小鼠是否也表现出对自发性疾病和由T细胞转移诱导的疾病的增强的易感性。 公共卫生关系：肠道充满了微生物，在肠道中发现的微生物的数量和种类可能是肠道慢性炎症性疾病（如炎症性肠病）的重要因素。虽然许多研究都集中在肠道细菌如何被免疫系统检测到，但对肠道真菌如何被检测到知之甚少。这项研究旨在确定小鼠肠道中发现的真菌库，并使用缺乏特定基因的小鼠来了解免疫系统如何与肠道真菌相互作用。