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

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。在导师布鲁斯利维博士的指导下， Cagnina博士的长期目标是获得必要的知识和技能，以发展成为一个独立的 他是一位物理学家兼科学家，同时为理解对曲霉菌的免疫反应做出了重大贡献。 曲霉菌属是普遍存在的霉菌，其在免疫受损或异常的宿主中引起临床疾病。 粘膜防御中性粒细胞在宿主防御这种病原体中起着关键作用，但对它的作用知之甚少。 在这种情况下，这些细胞的贡献超出了它们的直接杀微生物作用。我们先前已经表明 在宿主对肺中曲霉菌的反应过程中，中性粒细胞减少导致运输和成熟缺陷， 炎症单核细胞衍生的树突状细胞。在本提案的初步数据中，我们报告说， 中性粒细胞活性氧产生的缺乏足以诱导这种表型;在宿主中， 由于不能产生活性氧，炎性树突状细胞募集和肺损伤都是 依赖于TNF;并且中性粒细胞减少症损害针对病原体的保护性免疫的发展。 因此，我们试图测试的假设，在响应曲霉，活性氧物种依赖 中性粒细胞向炎性树突细胞的信号传导介导（a）对急性肺损伤的保护和（B） 产生针对曲霉菌的保护性适应性免疫。我们将在两个具体目标下对此进行测试：（1） 确定在先天性免疫应答过程中，嗜中性粒细胞衍生的ROS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免疫反应的发展中的作用。 对曲霉菌的适应性免疫。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。

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.