The Role of SP-A in Pulmonary Host Defense

描述(由申请人提供)：微生物侵入宿主之后，会发生一系列旨在控制和解决随后感染的事件。 对这些病原体的一线防御涉及到先天的成分 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。在缺乏血清来源的情况下 调理素在非炎症肺中的清除依赖于巨噬细胞表面 参与病原体的受体和肺特异性调理素 内部化。最近的证据表明，可溶性肺特异性 表面活性物质相关蛋白A(SP-A)等凝集素参与 清除了一些病原体。我们最近的工作重点是 表面活性蛋白A(SP-A)的作用研究 肺中表面活性物质相关蛋白，在分枝杆菌摄取和 通行证。我们已经在初步研究中表明，牛分枝杆菌卡介苗 巨噬细胞对禽分枝杆菌的内化作用 SP-A的光学电离然而，尽管SP-A增加了对摄入卡介苗的杀伤力 通过一氧化氮依赖途径，鸡分枝杆菌中SP-A的存在 内化对禽类微囊藻的存活没有影响。这个项目的目标是 探讨SP-A对分枝杆菌巨噬细胞内存活的影响。 我们建议研究分枝杆菌巨噬细胞中的几个步骤。 SP-A可能干扰沙门氏菌生存策略的入侵过程 病原体。我们的假设是：1)SP-A促进巨噬细胞内杀伤 结核分枝杆菌和卡介苗，通过改变吞噬过程中的特定步骤； 2)SP-A可促进禽类微囊藻的摄取，但对细胞内的摄取无影响 生死存亡。我们的研究将集中于三个具体目标：确定 SP-A改变内化分枝杆菌的细胞内运输，以 表征巨噬细胞内激活的信号通路 SP-A-导致产生肿瘤坏死因子和一氧化氮的分枝杆菌复合体， 探讨SP-A在分枝杆菌体内清除中的作用。它是 预期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，以及分枝杆菌如何 肺蛋白SP-A可能克服这种逃逸导致分枝杆菌增强 杀戮。

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.