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（由申请方提供）：呼吸道免疫系统每天清除数百个空气中的烟曲霉孢子（分生孢子）。肺中未经检查的孢子萌发导致侵袭性曲霉病（IA），这是免疫受损宿主中感染性发病率和死亡率的主要原因。除了肺泡巨噬细胞和募集的中性粒细胞，我们发现在肺动脉粥样硬化后，表达趋化因子受体CCR 2的单核细胞快速流入。烟曲霉菌攻毒。募集的单核细胞形成单核细胞来源的CD 11b + DC，将真菌抗原转运至引流淋巴结，并促进肺中真菌特异性CD 4 T细胞的启动。CCR 2表达细胞的消融导致真菌清除延迟和真菌特异性CD 4 T细胞应答的丧失。 为了探究单核细胞介导的宿主防御机制，我们开发了一种新的荧光A。烟曲霉菌株来可视化真菌摄取并区分肺中宿主白细胞内的活的和灭活的真菌细胞。通过这种方法，我们研究了一种单核细胞功能模型，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CARD 9和MyD 88整合了来自C型凝集素（CTL）和Toll样受体（TLR）的信号，以及来自细胞内NOD样受体（NLR）NLRP 3的信号。拟议的工作的基本原理是，它将提供一个全面的看法单核细胞及其衍生物在宿主防御吸入真菌孢子。 该提议的基础假设是单核细胞形成细胞抗真菌效应系统，其通过与真菌细胞的直接相互作用以及来自CTL、TLR和NLR信号传导途径的输入来形成，以指导肺中的先天性和适应性抗真菌免疫应答。目的是（1）确定单核细胞活化的机制和对免疫活性和免疫缺陷宿主中真菌细胞杀伤的贡献，以及（2）确定CARD 9、MyD 88和NLRP 3依赖性信号对感染结果、单核细胞依赖性先天性和适应性免疫功能以及协调中性粒细胞快速募集至感染气道的相对贡献。 实验设计将使我们能够比较单核细胞与其他免疫细胞亚群的功能，并描述在启动免疫反应的A。烟熏。拟议的研究作为一个模型，在体内荧光为基础的方法，解剖宿主-病原体相遇的双边细胞的结果。