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

• 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
• 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

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 和淋巴细胞。迄今为止，信号传导受体和途径尚不完全清楚。信令 淋巴细胞分子家族 (SLAMF) 受体在造血细胞和肺中广泛表达 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。我们最近报道了 在皮炎芽生菌 (Bd) 肺部感染期间，先天性需要 SLAMF1 免疫并且对于启动疫苗诱导的 CD4+ T 细胞是可有可无的。在初步数据中，我们发现 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 用于体外杀灭。这些发现表明外在的 SLAMF1 依赖性信号激活吞噬细胞杀死 体内酵母。 在此应用中，我们建议阐明 SLAMF1 受体在何处以及如何赋予吞噬细胞以 在肺部真菌感染期间杀死体内酵母菌的能力。我们假设先天淋巴细胞和 CCR2+ 单核细胞是 SLAMF1 介导的中性粒细胞激活所必需的。我们还假设 SLAMF1 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。我们提供强有力的初步数据 支持我们的假设。通过使用一组针对 17 种肺白细胞群的抗体， 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 感染后。我们在目标 1 中的工作计划提供了阐明 SLAMF1 对以下方面的要求的方法： 淋巴、骨髓或基质细胞，用于激活嗜中性粒细胞杀死酵母。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最有效的效应器。这些知识将提供基础 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。