Cellular and molecular mechanisms involving SLAMF1 during pulmonary fungal infection

肺部真菌感染过程中涉及SLAMF1的细胞和分子机制

基本信息

批准号：
10738468
负责人：
Marcel Wuethrich
金额：
$ 19.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738468
关键词：
Abbreviations Address Alveolar Antibodies Blastomyces dermatitidis Bone Marrow CD4 Positive T Lymphocytes Cause of Death Cells Colony-forming units Data Defect Dendritic Cells Development Effector Cell Endowment Epithelial Cells Exclusion Family Future Growth Hematopoietic Hour Immune In Vitro Infection Innate Immune Response Knowledge Leukocytes Lung Lung infections Lymphocyte Lymphoid Cell Mediating Medical Microbe Modeling Molecular Mucous Membrane Mus Mycoses Myeloid Cells Natural Immunity Natural Killer Cells Neutrophil Activation Nitric Oxide Pathway interactions Phagocytes Pharmaceutical Preparations Population Production Publishing Reactive Oxygen Species Receptor Signaling Reporting Resistance Role Signal Transduction Stains Stromal Cells T-Lymphocyte Testing Therapeutic United States Vaccines Wild Type Mouse Work Yeasts antimicrobial combat design fungus in vivo innovation insight microbial monocyte mouse model neutrophil novel novel therapeutic intervention pathogen pathogenic fungus pathogenic microbe receptor respiratory restraint sensor therapeutically effective vaccine development

项目摘要

PROJECT SUMMARY/ABSTRACT Lung cellular resistance against microbes requires a signaling network involving stroma and innate myeloid and lymphoid cells. To date, the signaling receptors and pathways are incompletely understood. Signaling Lymphocyte Molecule Family (SLAMF) receptors are widely expressed among hematopoietic cells and lung epithelial cells making them ideal candidates to orchestrate phagocyte killing of microbes. We recently reported that during pulmonary infection with the fungus Blastomyces dermatitidis (Bd), SLAMF1 is required for innate immunity and dispensable for priming vaccine-induced CD4+ Tcells. In preliminary data, we found that SLAMF1 is required for killing of the yeast by neutrophils and monocytes in vivo, but the receptor is dispensible for killing in vitro. These findings suggest that extrinsic, SLAMF1 dependent signals activate phagocytes to kill yeast in vivo. In this application, we propose to elucidate where and how SLAMF1 receptors endow phagocytes with the ability to kill yeast in vivo during pulmonary fungal infection. We hypothesize that innate lymphocytes and CCR2+ monocytes are required for SLAMF1-mediated neutrophil activation. We also posit that SLAMF1 mediates its function through homophilic (SLAMF1:SLAMF1) interactions between innate lymphocytes and monocytes or through direct sensing of the yeast by SLAMF1. We provide strong preliminary data to support our hypotheses. By using a panel of antibodies directed against 17 pulmonary leukocyte populations, we found SLAMF1 staining on CD4+TCR+, TCR+, MAIT cells and Ly6Chi CCR2+ monocytes at 16 hours post-infection. Our workplan in Aim 1 offers approaches that will elucidate the requirement of SLAMF1 on lymphoid, myeloid or stromal cells for activation of neutrophil killing of yeast. In Aim 2, we will define the mode of SLAMF1 action by distinguishing between SLAMF1 homophilic interactions among cells that express the receptor vs. direct sensing of yeast by SLAMF1. Our work will identify new mechanisms of receptor-mediated activation of innate effector cells and lay the groundwork for subsequent studies to advance detailed mechanistic insight into how SLAMF1 orchestrates signaling and activation of neutrophils, as these cells are the most potent effector to combat fungal and other microbial pathogens. This knowledge will provide the basis for developing and designing new strategies for therapeutic treatments against fungi, and other pathogenic microbes that require innate immunity for pathogen restraint.

项目概要/摘要肺细胞对微生物的抵抗需要涉及基质和先天骨髓的信号网络迄今为止，信号传导受体和信号传导途径尚不完全清楚。淋巴细胞分子家族 (SLAMF) 受体在造血细胞和肺中广泛表达我们最近报道，上皮细胞使其成为协调吞噬细胞杀死微生物的理想候选者。在皮炎芽生菌 (Bd) 肺部感染期间，先天性需要 SLAMF1 在初步数据中，我们发现，免疫和启动疫苗诱导的 CD4+ T 细胞是可有可无的。 SLAMF1是体内中性粒细胞和单核细胞杀死酵母所必需的，但受体不是必需的这些发现表明，外源性 SLAMF1 依赖性信号可激活吞噬细胞进行杀伤。体内酵母。在本申请中，我们建议阐明 SLAMF1 受体在何处以及如何赋予吞噬细胞以在肺部真菌感染过程中，我们有能力杀死体内的酵母菌，并且具有先天淋巴细胞的能力。 CCR2+ 单核细胞是 SLAMF1 介导的中性粒细胞激活所必需的。通过先天淋巴细胞之间的同质 (SLAMF1:SLAMF1) 相互作用介导其功能和单核细胞或通过 SLAMF1 直接感测酵母，我们提供了强有力的初步数据。通过使用一组针对 17 种肺白细胞群的抗体，支持我们的假设。 16 小时时，我们发现 CD4+TCR+、TCR+、MAIT 细胞和 Ly6Chi CCR2+ 单核细胞上有 SLAMF1 染色我们在目标 1 中的工作计划提供了阐明 SLAMF1 要求的方法。淋巴、骨髓或基质细胞用于激活中性粒细胞杀死酵母菌。在目标 2 中，我们将定义模式。通过区分表达 SLAMF1 的细胞之间的 SLAMF1 同亲相互作用来了解 SLAMF1 的作用受体与 SLAMF1 直接感测酵母的比较我们的工作将确定受体介导的新机制。激活先天效应细胞，为后续研究推进细节奠定基础深入了解 SLAMF1 如何协调中性粒细胞的信号传导和激活，因为这些细胞对抗真菌和其他微生物病原体的最有效的效应器将提供基础。开发和设计针对真菌和其他病原体的治疗新策略需要先天免疫来抑制病原体的微生物。