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

项目摘要/摘要 这项提案概述了卡尼纳博士的五年培训计划，以建立独立的职业生涯。 肺部和重症监护医学的研究人员。在导师布鲁斯·利维博士的指导下， 卡尼纳博士的长期目标是获得必要的知识和技能，以发展成为一名独立的 内科医生兼科学家，同时在了解曲霉的免疫反应方面做出了重大贡献。 曲霉菌是常见的霉菌，在免疫功能受损或异常的宿主中会引起临床疾病。 粘膜防御。中性粒细胞在宿主对这种病原体的防御中起着关键作用，但人们对此知之甚少 这些细胞在这方面的贡献超出了它们的直接杀菌作用。我们之前已经展示了 在宿主对肺部曲霉菌的反应中，中性粒细胞减少会导致运输和成熟的缺陷 炎性单核细胞来源的树突状细胞。在这项提案的初步数据中，我们报告说 中性粒细胞活性氧产生不足足以诱导这种表型；在宿主中 不能产生活性氧物种，炎性树突状细胞募集和肺损伤 依赖于肿瘤坏死因子；中性粒细胞减少会损害对病原体的保护性免疫。 因此，我们试图检验这一假设，即在对曲霉菌的反应中，活性氧物种依赖 中性粒细胞信号转导炎性树突状细胞介导(A)保护急性肺损伤和(B) 针对曲霉菌的保护性适应性免疫的产生。我们将在两个具体目标下进行测试：(1) 确定中性粒细胞来源的ROS在先天感染过程中调节树突状细胞功能的机制 曲霉菌的免疫应答和(2)确定中性粒细胞ROS在保护性疾病发展中的作用 对曲霉的获得性免疫。拟议的研究与公共卫生相关，因为它定义了一个新的 一种重要的人类病原体的寄主防御机制，应该允许未来的发展 新的治疗方法或预防策略。

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 mentor Dr. Bruce Levy, the broad, long-term objective is for Dr. Cagnina to gain 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.