Initiation of the Immune Response to Aspergillus fumigatus

对烟曲霉的免疫反应的启动

• 批准号: 8735460
• 负责人: TOBIAS M HOHL
• 金额: $ 33.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-06 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735460
• 关键词: Ablation; Adaptor Signaling Protein; Alveolar Macrophages; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Bilateral; Breathing; C-Type Lectins; CD4 Positive T Lymphocytes; Cells; Epithelial; Experimental Designs; Fluorescence; Fungal Antigens; Fungal Spores; Germination; Hematopoietic; Host Defense; Host Defense Mechanism; ITGAM gene; Immune; Immune response; Immune system; Infection; Knowledge; Leukocytes; Link; Lung; Measures; Mediating; Modeling; Molecular Target; Morbidity - disease rate; Neutrophil Infiltration; Organism; Outcome; Pathway interactions; Patients; Population; Receptor Signaling; Recruitment Activity; Relative (related person); Reproduction spores; Role; Shapes; Signal Pathway; Signal Transduction; Source; System; T cell response; Toll-like receptors; Vaccination; Work; base; cell killing; cellular targeting; chemokine receptor; functional outcomes; fungus; immune function; improved; in vivo Model; insight; killings; lymph nodes; monocyte; mortality; neutrophil; novel; pathogen; receptor; respiratory; uptake

DESCRIPTION (provided by applicant): The respiratory immune system clears hundreds of airborne Aspergillus fumigatus spores (conidia) daily. Unchecked spore germination in the lung leads to invasive aspergillosis (IA), a major cause of infectious morbidity and mortality in immune compromised hosts. Beyond resident alveolar macrophages and recruited neutrophils, we identified a rapid influx of chemokine receptor CCR2-expressing monocytes following pulmonary A. fumigatus challenge. Recruited monocytes form monocyte-derived CD11b+ DCs, transport fungal antigen to draining lymph nodes, and facilitate the priming of fungus-specific CD4 T cells in the lung. Ablation of CCR2-expressing cells results in delayed fungal clearance and loss of fungus-specific CD4 T cell responses. To interrogate monocyte-mediated host defense mechanisms triggered by the direct encounter with fungal cells, we developed a novel fluorescent A. fumigatus strain to visualize fungal uptake and distinguish viable and inactivated fungal cells within host leukocytes in the lung. With this approach, we examine a model of monocyte function that links cell activation and effector mechanisms to fungal uptake and that integrates signals from C-type lectin (CTL) and Toll-like receptors (TLRs) via the adaptor proteins CARD9 and MyD88 and from the intracellular NOD-like receptor (NLR) NLRP3. The rationale for the proposed work is that it will provide a comprehensive view of monocytes and their derivatives in host defense against inhaled fungal spores. The hypothesis that underlies this proposal is that monocytes form a cellular antifungal effector system shaped by direct interactions with fungal cells and input from CTL, TLR, and NLR signaling pathways to direct innate and adaptive antifungal immune responses in the lung. The aims will (1) define the mechanism of monocyte activation and contribution to fungal cell killing in immune competent and neutropenic hosts and (2) determine the relative contribution of CARD9-, MyD88-, and NLRP3-dependent signals on the outcome of infection, on monocyte-dependent innate and adaptive immune functions, and on orchestrating rapid neutrophil recruitment to infected airways. The experimental design will enable us to compare monocytes functionally with other immune cell subsets and to describe essential steps in the initiation of the immune response to A. fumigatus. The proposed studies serve as a model for in vivo fluorescence-based approaches that dissect the bilateral cellular outcomes of host-pathogen encounters.

描述（由申请人提供）：呼吸道免疫系统清除了数百个空气中的曲霉孢子孢子（分生孢子）。肺中未经检查的孢子发芽导致侵袭性曲霉菌病（IA），这是免疫损害宿主传染性发病和死亡率的主要原因。除了居民肺泡巨噬细胞和招募的中性粒细胞之外，我们还发现了肺化曲霉挑战后，趋化因子受体CCR2表达单核细胞的迅速涌入。招募的单核细胞形成单核细胞来源的CD11b+ DC，将真菌抗原转运至排水淋巴结，并促进肺中真菌特异性CD4 T细胞的启动。表达CCR2细胞的消融导致真菌清除延迟和真菌特异性CD4 T细胞反应的丧失。 为了询问由真菌细胞直接相遇触发的单核细胞介导的宿主防御机制，我们开发了一种新型的荧光烟曲霉菌株，以可视化真菌摄取并区分肺中宿主白细胞中的可行和灭活的真菌细胞。通过这种方法，我们检查了单核细胞功能的模型，该模型将细胞活化和效应机制与真菌摄取联系起来，并通过衔接蛋白（CTL）和Toll-like受体（TLR）整合信号，并通过适配器蛋白Card9和MyD88和MyD88以及来自细胞内的Nodelular Nodelular Nodelular Nod-nod-nod-nod-nod-nod-nod-like受体（nlr）NLRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR。拟议的工作的理由是，它将在宿主防御剂中对吸入真菌孢子的宿主防御中的单核细胞及其衍生物提供全面的看法。 该提议构成的基础的假设是，单核细胞形成了一种细胞抗真菌性效应器系统，该系统由与真菌细胞直接相互作用以及CTL，TLR和NLR信号传导途径的输入形成，以直接定用和适应性抗真菌免疫反应。目的将（1）定义单核细胞激活的机制以及对免疫能力和中性粒细胞宿主中真菌细胞杀死的贡献，以及（2）确定Card9-，MyD88-和NLRP3信号的相对贡献，依赖于感染的结果，对单核依赖性依赖性依赖性和适应性的免疫功能以及对移动的影响，并依赖于感染的影响。 实验设计将使我们能够将单核细胞与其他免疫细胞子集进行比较，并描述启动对烟曲霉的免疫反应的基本步骤。拟议的研究是基于体内荧光的方法的模型，该方法剖析了宿主 - 病原体相遇的双侧细胞结局。