Initiation of the Immune Response to Aspergillus fumigatus

对烟曲霉的免疫反应的启动

• 批准号: 8274640
• 负责人: TOBIAS M HOHL
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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/8274640
• 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）：呼吸道免疫系统每天清除空气中数百个烟曲霉孢子（分生孢子）。肺部不受控制的孢子萌发会导致侵袭性曲霉病 (IA)，这是免疫受损宿主感染发病和死亡的主要原因。除了驻留的肺泡巨噬细胞和招募的中性粒细胞外，我们还发现在肺部烟曲霉攻击后，表达趋化因子受体 CCR2 的单核细胞迅速涌入。招募的单核细胞形成单核细胞衍生的 CD11b+ DC，将真菌抗原转运至引流淋巴结，并促进肺部真菌特异性 CD4 T 细胞的启动。 CCR2 表达细胞的消融会导致真菌清除延迟和真菌特异性 CD4 T 细胞反应丧失。 为了探究由直接接触真菌细胞而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荧光烟曲霉菌株，以可视化真菌的摄取并区分肺部宿主白细胞内的活真菌细胞和灭活真菌细胞。通过这种方法，我们检查了单核细胞功能模型，该模型将细胞激活和效应机制与真菌摄取联系起来，并通过接头蛋白 CARD9 和 MyD88 整合来自 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) NLRP3。拟议工作的基本原理是，它将提供单核细胞及其衍生物在宿主防御吸入真菌孢子方面的全面视图。 这一提议的假设是，单核细胞形成一个细胞抗真菌效应系统，该系统通过与真菌细胞的直接相互作用以及来自 CTL、TLR 和 NLR 信号通路的输入来指导肺部的先天性和适应性抗真菌免疫反应而形成。目标将 (1) 确定免疫活性和中性粒细胞减少宿主中单核细胞激活的机制以及对真菌细胞杀伤的贡献，以及 (2) 确定 CARD9、MyD88 和 NLRP3 依赖性信号对感染结果的相对贡献，依赖于单核细胞的先天和适应性免疫功能，以及协调中性粒细胞快速招募到受感染的气道。 实验设计将使我们能够将单核细胞与其他免疫细胞亚群进行功能比较，并描述烟曲霉免疫反应启动的基本步骤。拟议的研究作为基于体内荧光的方法的模型，剖析宿主与病原体相遇的双边细胞结果。