The Role of SP-A in Pulmonary Host Defense

描述（由申请方提供）：遵循微生物侵入宿主 通过一系列旨在控制和解决随后感染的事件。 针对这些病原体的第一线防御涉及先天免疫系统的组成部分， 免疫系统在肺中，肺泡巨噬细胞是主要的细胞成分 负责清除吸入的病原体。在缺乏血清来源的 调理素在非炎症肺中的清除依赖于巨噬细胞表面 受体和肺特异性调理素参与病原体 内化最近的证据表明，可溶性肺特异性 凝集素如表面活性剂相关蛋白A（SP-A）参与了 清除一些病原体。我们最近工作的重点是 研究表面活性蛋白A（SP-A）的作用， 肺中的表面活性剂相关蛋白，分枝杆菌的摄取， 间隙我们已经在初步研究中表明， 巨噬细胞对鸟分枝杆菌的内化作用通过 用SP-A调理。然而，尽管SP-A增加了摄入的BCG的杀伤力， 通过一氧化氮依赖性途径，M.鸟 内化对M.鸟类生存这个项目的目标是 检测SP-A对分枝杆菌巨噬细胞内存活的影响。 我们建议检查分枝杆菌-巨噬细胞中的几个步骤 SP-A可能会干扰入侵过程中的生存策略， 病原体我们的假设是：1）SP-A促进巨噬细胞内杀伤 M.通过改变吞噬过程中的特定步骤来抑制结核病和BCG; 2）SP-A对M.但对细胞内 生存我们将集中研究三个具体目标： SP-A改变内化分枝杆菌的细胞内运输， 表征巨噬细胞内信号通路激活 SP-A-分枝杆菌复合物导致TNF和一氧化氮的产生， 并检测SP-A在体内清除分枝杆菌中的作用。是 预计这些研究的结果将有助于理解 分枝杆菌如何逃脱宿主巨噬细胞的正常破坏，以及 肺蛋白SP-A可能会克服这种逃逸，从而增强分枝杆菌 杀人

DESCRIPTION (provided by applicant): Microbial invasion of the host is followed by a series of events designed to contain and resolve the ensuing infection. First line defense against these pathogens involves components of the innate immune system. In the lung, alveolar macrophages are a major cellular component responsible for clearance of inhaled pathogens. In the absence of serum-derived opsonins in the non-inflamed lung, clearance is dependent on macrophage surface receptors and lung-specific opsonins that participate in pathogen internalization. Recent evidence has demonstrated that soluble lung-specific lectins such as surfactant associated protein A (SP-A) participate in the clearance of a number of pathogens. The focus of our recent work has been the study of the role of surfactant protein A (SP-A), one of four known surfactant-associated proteins in the lung, in mycobacterial uptake and clearance. We have shown in preliminary studies that Mycobacterium bovis BCG and Mycobacterium avium internalization by macrophages is enhanced by opsonization with SP-A. However, while SP-A increases killing of ingested BCG through a nitric oxide-dependent pathway, the presence of SP-A during M. avium internalization has no effect on M. avium survival. The goal of this project is to examine the effect of SP-A on the intramacrophage survival of mycobacteria. We are proposing to examine several steps in the mycobacterial-macrophage invasion process where SP-A might interfere with the survival strategies of the pathogen. Our hypotheses are 1) that SP-A promotes intra-macrophage killing of M. tuberculosis and BCG by altering a specific step in the phagocytic process; and 2) that SP-A enhances M. avium uptake but has no effect on intracellular survival. We will focus our studies on three specific aims: to determine if SP-A alters the intracellular trafficking of internalized mycobacteria, to characterize the intramacrophage signaling pathways activated by SP-A-mycobacterial complexes that result in production of TNF and nitric oxide, and to examine the role of SP-A in the in vivo clearance of mycobacteria. It is anticipated that results from these studies will contribute to an understanding of how mycobacteria escape normal destruction by host macrophages, and how the lung protein SP-A might overcome this escape leading to enhanced mycobacterial killing.