Dectin-1 Signaling Mechanisms

Dectin-1 信号传导机制

• 批准号: 8629147
• 负责人: David M. Underhill
• 金额: $ 42.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629147
• 关键词: Adaptor Signaling Protein; Antifungal Agents; Antigen Presentation; Antigen Presentation Pathway; Antigens; Aspergillus fumigatus; Autophagocytosis; Binding; C-Type Lectins; Candida albicans; Cell Wall; Cells; Complex; Dendritic Cells; Effectiveness; Fungal Antigens; Fungal Vaccines; Glucans; Host Defense; Human; Immune response; Immunity; Immunologic Receptors; In Vitro; Infection; Inflammatory; Inflammatory Response; Interleukin-1; Knockout Mice; Lead; Lung; Mediating; Microscopy; Modeling; Molecular; Mus; Mycoses; Myelogenous; Natural Immunity; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Polysaccharides; Process; Production; Proteins; Reactive Oxygen Species; Receptor Activation; Recruitment Activity; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Synapses; T-Lymphocyte; Weight; Work; Yeasts; adaptive immunity; caspase-8; cytokine; dectin 1; fungus; in vivo; killings; macrophage; microbial; microbicide; novel; particle; pathogen; public health relevance; receptor; secretion process; src-Family Kinases; vaccine development

DESCRIPTION (provided by applicant): Dectin-1 is an innate immune receptor expressed by myeloid phagocytes such as macrophages and dendritic cells that is essential for effective host defense against fungal infections. Dectin-1 recognizes the ¿-1,3-glucan polysaccharide that makes up as much as half the dry weight of fungal cell walls, and activation of the receptor triggers phagocytosis, production of microbicidal reactive oxygen species, and production of a host of pro- inflammatory cytokines. Dectin-1 is one of only a few receptors so far shown to be sufficient for triggering phagocytosis, and it has thus become an important model for understanding how such receptors work. This renewal project focuses on further understanding the mechanisms of Dectin-1 signaling. We have previously shown that upon binding to fungal cells Dectin-1 is concentrated into a "phagocytic synapse" that permits activation of inflammatory signaling. We have further shown that Dectin-1 signaling leads to formation of phagosomes that recruit LC3, a protein that is well-known to participate in autophagy, but its role on traditional phagosomes is less clear. We have shown that LC3 recruitment to phagosomes enhances processing and presentation of antigens from these compartments on MHCII, and other investigators have shown that these phagosomes are more microbicidal. In addition, we and others have observed that Dectin-1 signaling drives activation of the inflammasome, a complex that facilitates processing and secretion of the pro- inflammatory cytokine IL-1¿. This signal requires CARD9 and caspase-8 activity, features that appear to be unique to Dectin-1. In this project, we will define this model signaling pathway in three aims. In aim one, we will define the mechanisms by which Dectin-1 signaling and LC3 influence phagosome maturation in order to favor efficient presentation of antigens in vitro and in vivo. In aim two we will determine the mechanisms by which Dectin-1 signaling and phagocytosis lead to activation of an unusual Card9-related inflammasome for inflammatory cytokine production and explore the role of this process in activation of immune responses in vitro and in vivo. In aim 3 we will explore the role of "LC3-associated phagocytosis" and Card9-related inflammasome activation during infection of mice with the prevalent human fungal pathogens Candida albicans and Aspergillus fumigatus.

描述（由适用提供）：Dectin-1是由髓样吞噬细胞（例如巨噬细胞和树突状细胞）表达的先天免疫受体，这对于有效防御真菌感染至关重要。 Dectin-1识别€-1,3-葡聚糖多糖，该多糖占真菌细胞壁干重的一半，受体的激活触发了吞噬作用，产生了微生物活性活性氧，以及产生大量炎性细胞因子的宿主。 Dectin-1是迄今为止仅有的少数几个受体之一，足以触发吞噬作用，因此它已成为了解这种受体如何工作的重要模型。该更新项目的重点是进一步理解Dectin-1信号传导的机制。我们先前已经表明，与真菌细胞结合后，Dectin-1被集中在允许激活炎症信号传导的“吞噬突触”中。我们进一步表明，dectin-1信号传导导致形成吞噬体的吞噬体，该吞噬体募集了LC3，这是一种众所周知的参与自噬的蛋白质，但其在传统吞噬体上的作用尚不清楚。我们已经表明，对吞噬体的LC3募集增强了从MHCII上这些隔室的抗原的加工和表现，而其他研究者则表明，这些吞噬体是更微生物剂。此外，我们和其他人观察到Dectin-1信号传导驱动炎症体的激活，这是一种促进促炎性细胞因子IL-1缺的复合物的复合物。该信号需要card9和caspase-8活性，这些功能似乎是dectin-1独有的。在这个项目中，我们将以三个目标定义此模型信号通路。在目标中，我们将定义Dectin-1信号传导和LC3影响吞噬体成熟的机制，以促进体外和体内抗原的有效表现。在目标二中，我们将确定dectin-1信号传导和吞噬作用导致与炎症细胞因子产生的不寻常Card9相关炎症体激活的机制，并探索该过程在体外和体内激活免疫调查中的作用。目标 3我们将探讨在患有流行的人类真菌病原体念珠菌和烟曲霉的小鼠感染期间，“与LC3相关的吞噬作用”和与Card9相关的炎性体激活的作用。