Mechanisms of anti-fungal immunity mediated by SCARF1 and CD36

SCARF1和CD36介导的抗真菌免疫机制

• 批准号: 8260822
• 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
• 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/8260822
• 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

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（由申请人提供）：巨噬细胞是宿主对真菌感染的抗性的重要细胞，巨噬细胞的真菌识别会触发吞噬作用，细胞内杀伤，诱导炎症细胞因子和趋化因子和趋化因子和趋化因子和适应性免疫反应的启动。尚不完全了解所有介导真菌病原体结合和吞没的巨噬细胞受体以及由调节抗真菌免疫力的真菌病原体触发的信号传导途径。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理的影响。 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，并通过TLRS信号导致产生炎症介体。我们假设清道夫受体家族的成员是一种指导病原体和自我起源的多含电液配体的吸收和清除的PRR，与TLR合作，以识别真菌病原体。该假设是基于初步发现，即HEK293细胞中与TLR2/6共表达Scarf1或CD36会导致NF：B激活增强，以响应Neoformans刺激。此外，我们发现缺乏SCARF1，CD36或TLR2表达的巨噬细胞响应Neoformans刺激而产生细胞因子的能力降低。在此提案中，我们将定义由Scarf1和CD36在体外和体内介导的抗真菌免疫的机制。具体而言，我们将（1）确定Scarf1和CD36在促进真菌病原体促进TLR信号中的作用，（2）确定Scarf1，CD36和TLR2信号在小鼠中真菌发病机理中的贡献，（3）确定Scarf1和CD36表达是否需要树枝状细胞的表达。识别调节对真菌病原体巨噬细胞炎症反应的受体和信号通路将为这些细胞在真菌发病机理中的作用提供宝贵的见解，并可能是新型药物设计的治疗靶标。 公共卫生相关性：迫切需要开发新的抗真菌药物，以抵抗增加的真菌感染和耐药菌物种的增加。在真菌感染中，炎症反应是由巨噬细胞介导的，这些巨噬细胞对真菌细胞的结合，吞噬和杀死至关重要。识别调节对真菌病原体巨噬细胞炎症反应的受体和信号通路将为这些细胞在真菌发病机理中的作用提供宝贵的见解，并可能是新型药物设计的治疗靶标。