Mechanisms of anti-fungal immunity mediated by SCARF1 and CD36

SCARF1和CD36介导的抗真菌免疫机制

基本信息

批准号：
8065510
负责人：
TERRY K MEANS
金额：
$ 41.63万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8065510
关键词：
Address Affect Amino Acids Antibodies Antifungal Agents Aspergillus fumigatus Binding Brain CD36 gene CD4 Positive T Lymphocytes Candida albicans Cell Maturation Cell Wall Cells Cryptococcus neoformans Cultured Cells Data Dendritic Cells Development Drug Design Drug resistance Family Fluorescence Resonance Energy Transfer Goals Grant Host resistance Human Imaging Techniques Immune Immune response Immune system Immunity Immunocompromised Host In Vitro Individual Infection Inflammation Mediators Inflammatory Inflammatory Response Kidney Life Ligands Liver Lung Lymphocyte Lymphoid Tissue Macrophage Activation Mammalian Cell Measures Mediating Modeling Molds Molecular Morbidity - disease rate Mus Mycoses Organ Pathogenesis Pathway interactions Pattern recognition receptor Phagocytosis Pharmaceutical Preparations Predisposition Production Proteins Receptor Signaling Role Signal Pathway Signal Transduction Site-Directed Mutagenesis Spleen Surface T-Cell Activation T-Lymphocyte TLR2 gene Testing Toll-like receptors Wild Type Mouse Yeasts base chemokine combat cytokine fungus in vivo inflammatory marker insight killings lymph nodes macrophage mannose receptor member microbial mortality new therapeutic target novel pathogen public health relevance receptor response scavenger receptor small hairpin RNA uptake

项目摘要

DESCRIPTION (provided by applicant): Macrophages are important cells in the host resistance to fungal infections, and fungal recognition by macrophages triggers phagocytosis, intracellular killing, induction of inflammatory cytokines and chemokines, and initiation of the adaptive immune response. All the macrophage receptors that mediate binding and engulfment of fungal pathogens and the signaling pathways triggered by fungal pathogens that regulate anti-fungal immunity are not fully understood. Our long-term goals are to identify the molecular mechanisms of macrophage activation by fungal pathogens and the impact of these pathways on fungal pathogenesis. Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) that mediate the recognition of many microbial products, and signaling through TLRs leads to the production of inflammatory mediators. We hypothesize that members of the scavenger receptor family, a class of PRRs that direct the uptake and clearance of polyanionic ligands of both pathogen and self origin, collaborate with TLRs in the recognition of fungal pathogens. This hypothesis is based on preliminary findings that co-expression of SCARF1 or CD36 with TLR2/6 in HEK293 cells results in enhanced NF:B activation in response to Cryptococcus neoformans stimulation. In addition, we found that macrophages deficient for SCARF1, CD36, or TLR2 expression had a reduced capacity to produce cytokines in response to C. neoformans stimulation. In this proposal, we will define the mechanisms of anti-fungal immunity mediated by SCARF1 and CD36 in vitro and in vivo. Specifically, we will (1) determine the role of SCARF1 and CD36 in facilitating TLR signaling by fungal pathogens, (2) Determine the contribution of SCARF1, CD36, and TLR2 signaling in fungal pathogenesis in mice, and (3) Determine whether SCARF1 and CD36 expression is required for dendritic cell maturation by fungal pathogens. Identifying the receptors and signaling pathways involved in regulating macrophage inflammatory responses to fungal pathogens will provide valuable insight into the role of these cells in fungal pathogenesis and possibly serve as therapeutic targets for novel drug design. PUBLIC HEALTH RELEVANCE: There is a pressing need for the development of new anti-fungal drugs to combat the increasing number of fungal infections and the increase in drug-resistant fungal species. In fungal infections, the inflammatory response is mediated by macrophages that are critical in the binding, engulfment, and killing of fungal cells. Identifying the receptors and signaling pathways involved in regulating macrophage inflammatory responses to fungal pathogens will provide valuable insight into the role of these cells in fungal pathogenesis and possibly serve as therapeutic targets for novel drug design.

描述（申请人提供）：巨噬细胞是宿主抵抗真菌感染的重要细胞，巨噬细胞对真菌的识别会引发吞噬作用、细胞内杀伤、诱导炎性细胞因子和趋化因子以及启动适应性免疫反应。所有介导真菌病原体结合和吞噬的巨噬细胞受体以及真菌病原体触发的调节抗真菌免疫的信号通路尚不完全清楚。我们的长期目标是确定真菌病原体激活巨噬细胞的分子机制以及这些途径对真菌发病机制的影响。 Toll 样受体 (TLR) 是一类模式识别受体 (PRR)，可介导许多微生物产物的识别，通过 TLR 发出的信号会导致炎症介质的产生。我们假设清道夫受体家族的成员（一类 PRR，指导病原体和自身来源的聚阴离子配体的摄取和清除）与 TLR 合作识别真菌病原体。该假设基于初步发现，即 HEK293 细胞中 SCARF1 或 CD36 与 TLR2/6 的共表达导致响应新型隐球菌刺激而增强 NF:B 激活。此外，我们发现缺乏 SCARF1、CD36 或 TLR2 表达的巨噬细胞响应新生隐球菌刺激而产生细胞因子的能力降低。在本提案中，我们将定义 SCARF1 和 CD36 体外和体内介导的抗真菌免疫机制。具体来说，我们将 (1) 确定 SCARF1 和 CD36 在促进真菌病原体 TLR 信号传导中的作用，(2) 确定 SCARF1、CD36 和 TLR2 信号传导在小鼠真菌发病机制中的贡献，以及 (3) 确定 SCARF1 和 CD36 是否CD36 表达是真菌病原体树突状细胞成熟所必需的。鉴定参与调节巨噬细胞对真菌病原体炎症反应的受体和信号通路将为了解这些细胞在真菌发病机制中的作用提供有价值的见解，并可能作为新药物设计的治疗靶点。公共卫生相关性：迫切需要开发新的抗真菌药物来对抗日益增加的真菌感染和耐药真菌物种的增加。在真菌感染中，炎症反应由巨噬细胞介导，巨噬细胞对于结合、吞噬和杀死真菌细胞至关重要。鉴定参与调节巨噬细胞对真菌病原体炎症反应的受体和信号通路将为了解这些细胞在真菌发病机制中的作用提供有价值的见解，并可能作为新药物设计的治疗靶点。