Host immunity to commensal gut fungi

宿主对共生肠道真菌的免疫力

• 批准号: 8690040
• 负责人: David M. Underhill
• 金额: $ 43.89万
• 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/8690040
• 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; pyrosequencing; 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.

描述（由申请人提供）：许多研究已经证明特定肠道细菌在调节粘膜免疫和指导组织发育和修复方面发挥着重要作用，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”通常可以互换使用。更好地了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良好的了解，并拥有一个可以操纵对肠道真菌的免疫反应的模型。我的实验室一直在研究 β-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 通过一种称为 CARD9 的细胞内信号传导接头分子发出炎症反应信号，CARD9 是一种蛋白质，其特定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受到 DSS 诱导的急性结肠炎的影响，并且这种敏感性的增强是由于肠道真菌所致。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微生物区系，并已鉴定出数百种肠道真菌。因此，我们正在开发一种对肠道中真菌的数量和类型的认识，以及一种可以操纵对肠道真菌的免疫反应的模型。我们的总体假设是，β-葡聚糖受体 Dectin-1 负责调查肠道微生物群中的真菌，并协调宿主免疫反应，从而塑造微生物群并导致肠道炎症。我们将从四个目标来探讨这一假设。在 目标 1 我们将表征野生型、Dectin-1-/- 和 CARD9-/- 小鼠在静息和炎症条件下的真菌微生物组。在目标 2 中，我们将定义 Decitn-1 在肠道真菌采样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 CARD9 的小鼠是否表现出与 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 CARD9 敲除小鼠是否也表现出对自发性疾病和 T 细胞转移诱导疾病的易感性增强。