Dectin-1 and Immunity Against Pneumocystis Carinii

Dectin-1 和卡氏肺孢子虫免疫

• 批准号: 7516394
• 负责人: Chad Steele
• 金额: $ 28.37万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516394
• 关键词: Adenoviruses; Adoptive Transfer; Alveolar Macrophages; Antigen Presentation; Antigens; Appendix; Area; Biological Assay; CXC Chemokines; Carbohydrates; Cells; Chad; Characteristics; Chimeric Proteins; Coculture Techniques; Data; Dendritic Cells; Environment; Equilibrium; Event; Excision; Glucans; Guanine Nucleotide Dissociation Inhibitors; Host Defense; Host Defense Mechanism; Human; ITAM; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunotherapeutic agent; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Interruption; Invaded; Knockout Mice; Lead; Lectin; Link; Lung; Lymphoid Tissue; Mediating; Modeling; Mus; Mutate; Natural Immunity; Organism; Pathogenesis; Pathway interactions; Phagocytes; Play; Pneumocystis carinii; Pneumonia; Polymerase Chain Reaction; Predisposition; Production; Proliferating; Protein Tyrosine Kinase; Research Personnel; Role; Signal Transduction; Site; Splenocyte; System; T-Cell Activation; T-Lymphocyte; Testing; Time; Tin; Tissues; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha; base; beta-Glucans; beta-glucan receptor; chemokine; concept; cytokine; dectin 1; extracellular; high throughput screening; in vivo; in vivo Model; insight; killings; lung injury; macrophage; macrophage inflammatory protein 2; mannose receptor; molecular recognition; mutant; novel; pathogen; programs; receptor; reconstitution; research study; response

DESCRIPTION (provided by applicant): Elimination of Pneumocystis carinii, a significant cause of pneumonia in immunocompromised individuals, from the pulmonary environment is the exclusive responsibility of the alveolar macrophage. However, due to P. carinii's inability to be stably cultured in vitro, to date, there has been no high-throughput assay of viability to elucidate innate cell-mediated host defense mechanisms against P. carinii. Using a novel in vitro killing assay, we discovered that recognition and subsequent non-opsonic killing of P. carinii by alveolar macrophages occurs via a newly described receptor for fungal beta-glucans, Dectin-1. Dectin-1 is a 28 kDa, type II transmembrane receptor that contains a single lectin-like carbohydrate recognition domain which recognizes beta 1,3-linked and beta 1,6-linked glucans. We also observed that the alveolar macrophage inflammatory response to P. carinii is mediated by Dectin-1 recognition. We further show that immature lung-derived dendritic cells express high levels of Dectin-1. Based on these studies, we hypothesize that Dectin-1 is required for non-opsonic alveolar macrophage effector function against P. carinii as well as dendritic cell-mediated activation of adaptive T cell responses against P. carinii. We will test this hypothesis with the following specific aims. Specific Aim 1: To test the concept that Dectin-1 mediated recognition of P. carinii is critical for alveolar macrophage host defense against P. carinii in vitro. Specific Aim 2: To test the concept that beta-glucan recognition is required for P. carinii-induced pulmonary inflammation. Specific Aim 3: To test the concept that interruption of Dectin-1 mediated P. carinii recognition increases susceptibility to lung infection with P. carinii. These studies will investigate a new fungal molecular recognition receptor and characterize its role, in vitro as well as in vivo, against the opportunistic fungal organism P. carinii and may provide new insight into how P. carinii is recognized by the immune system, which may lead to novel immunotherapeutic strategies to combat this devastating pulmonary infection.

描述（由申请人提供）：从肺环境中消除卡氏肺孢子虫（免疫功能低下个体肺炎的重要原因）是肺泡巨噬细胞的唯一责任。 然而，由于卡氏肺孢子虫不能在体外稳定培养，迄今为止，还没有高通量的生存力测定来阐明针对卡氏肺孢子虫的先天性细胞介导的宿主防御机制。使用一种新的体外杀伤试验，我们发现肺泡巨噬细胞对卡氏肺孢子虫的识别和随后的非调理素杀伤是通过一种新描述的真菌β-葡聚糖受体Dectin-1发生的。 Dectin-1是一种28 kDa的II型跨膜受体，含有单个凝集素样碳水化合物识别结构域，其识别β 1，3-连接和β 1，6-连接的葡聚糖。 我们还观察到肺泡巨噬细胞对卡氏肺孢子虫的炎症反应由Dectin-1识别介导。 我们进一步表明，未成熟的肺源性树突状细胞表达高水平的Dectin-1。 基于这些研究，我们假设Dectin-1是针对卡氏肺孢子虫的非调理素肺泡巨噬细胞效应子功能以及树突状细胞介导的针对卡氏肺孢子虫的适应性T细胞应答的活化所必需的。我们将通过以下具体目标来检验这一假设。 具体目标1：检测Dectin-1介导的卡氏肺孢子虫识别对于肺泡巨噬细胞宿主体外防御卡氏肺孢子虫至关重要的概念。 具体目标2：检验卡氏肺孢子虫诱导的肺部炎症需要β-葡聚糖识别的概念。 具体目标3：为了测试中断Dectin-1介导的卡氏肺孢子虫识别增加卡氏肺孢子虫肺部感染易感性的概念。 这些研究将研究一种新的真菌分子识别受体，并在体外和体内表征其对机会性真菌生物卡氏肺孢子虫的作用，并可能为卡氏肺孢子虫如何被免疫系统识别提供新的见解，这可能导致新的免疫策略来对抗这种毁灭性的肺部感染。