Regulation of dendritic cell function by neutrophil-derived reactive oxygen species in pulmonary aspergillosis

肺曲霉病中中性粒细胞衍生的活性氧对树突状细胞功能的调节

• 批准号: 9926917
• 负责人: Rebecca Elaine Cagnina
• 金额: $ 16.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-03 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926917
• 关键词: Acute Lung Injury; Allergic Bronchopulmonary Aspergillosis; Antibodies; Antigen-Presenting Cells; Apoptosis; Apoptotic; Aspergillosis; Aspergillus; Bone Marrow; CCL2 gene; Cell Maturation; Cell physiology; Cells; Cellular Immunity; Clinical; Critical Care; Cytotoxic agent; Dangerousness; Data; Defect; Dendritic Cells; Development; Disease; Future; Generations; Host Defense; Host Defense Mechanism; Human; Immune response; Immune system; Immunity; Immunocompromised Host; Impairment; Infection; Inflammatory; Inherited; Innate Immune Response; Knowledge; Lead; Link; Literature; Lung; Lung diseases; Mediating; Medicine; Memory; Mentors; Modeling; Molds; Mucous Membrane; Mus; Natural Immunity; Neutropenia; Organism; Pathway interactions; Patients; Phagocytosis; Phenotype; Physicians; Play; Prevention strategy; Production; Public Health; Reactive Oxygen Species; Regulation; Reporting; Research; Research Personnel; Role; Scientist; Signal Transduction; Site; Structure; T-Lymphocyte; TNF gene; Testing; Training Programs; Work; adaptive immunity; allergic response; career; draining lymph node; fungus; human pathogen; lung injury; microbicide; monocyte; mortality; neutrophil; novel; novel therapeutics; pathogen; recruit; response; secondary infection; skills; tissue injury; vaccine development

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year training program for Dr. Cagnina to establish a career as an independent investigator in Pulmonary and Critical Care Medicine. Under the guidance of co-mentors Drs. Borna Mehrad and Tom Braciale, our broad, long-term objective is for Dr. Cagnina to gain new the knowledge and skills necessary to evolve into an independent physician-scientist, while making significant contributions to understanding the immune response to Aspergillus. Aspergillus species are ubiquitous molds that cause clinical disease in hosts with impaired immunity or abnormal mucosal defenses. Neutrophils play a key role in host defenses against this pathogen but little is known about the contribution of these cells in in this context beyond their direct microbicidal role. We have previously shown that, during host response to Aspergillus in the lung, neutropenia results in a defect in the traffic and maturation of inflammatory monocyte-derived dendritic cells. In the preliminary data for this proposal, we report that deficiency in neutrophil reactive oxygen species production is sufficient to induce this phenotype; that, in hosts unable to generate reactive oxygen species, both the inflammatory dendritic cell recruitment and lung injury are dependent on TNF; and that neutropenia impairs the development of protective immunity against the pathogen. We therefore seek to test the hypothesis that in response to Aspergillus, reactive oxygen species-dependent neutrophil signaling to inflammatory dendritic cells mediates (a) protection from acute lung injury and (b) generation of protective adaptive immunity against Aspergillus. We will test this under two specific aims: (1) To identify the mechanism by which neutrophil-derived ROS modulates dendritic cell function during the innate immune response to Aspergillus and (2) To define the role of neutrophil ROS in the development of protective adaptive immunity against Aspergillus. The proposed studies are relevant to public health by defining a new mechanism of host defense against an important human pathogen that should allow for future development of novel therapeutics or preventative strategies.

项目总结/摘要 该提案概述了一个为期五年的培训计划，为卡格尼纳博士建立一个职业生涯作为一个独立的 肺和重症监护医学研究员。在共同导师Borna Mehrad博士的指导下， 和汤姆Braciale，我们广泛的，长期的目标是博士Cagnina获得新的知识和技能， 必须发展成为一个独立的物理学家，科学家，同时作出重大贡献， 了解对曲霉菌的免疫反应曲霉属是普遍存在的霉菌， 免疫力受损或粘膜防御异常的宿主的临床疾病。中性粒细胞在 宿主防御这种病原体，但很少有人知道这些细胞在这种情况下的贡献 除了直接的杀微生物作用之外。我们以前已经表明，在宿主对曲霉菌的反应过程中， 在肺中，中性粒细胞减少导致炎性单核细胞衍生的树突状细胞的运输和成熟缺陷， 细胞在这个建议的初步数据中，我们报告说，中性粒细胞活性氧缺乏， 产生足以诱导这种表型;即，在不能产生活性氧物质的宿主中， 炎性树突状细胞募集和肺损伤都依赖于TNF;中性粒细胞减少症 损害了对病原体的保护性免疫力的发展。因此，我们寻求测试 假设响应曲霉菌，活性氧物质依赖性中性粒细胞信号转导， 炎性树突状细胞介导（a）对急性肺损伤的保护和（B）保护性细胞的产生， 对曲霉菌的适应性免疫。我们将在两个具体目标下对此进行测试：（1）识别 嗜中性粒细胞衍生的ROS在先天免疫过程中调节树突状细胞功能的机制 （2）确定中性粒细胞活性氧在保护性适应性细胞发展中的作用。 对曲霉菌免疫。拟议的研究与公共卫生有关， 宿主对一种重要的人类病原体的防御机制，应该允许未来的发展， 新的治疗或预防策略。