Early host microbial interactions in S. aureus pneumonia

金黄色葡萄球菌是医院获得性肺炎的第二大病原体，也是严重社区获得性肺炎的重要病原体。肺炎既是急性肺损伤的重要前驱事件，也是ARDS最常见的致死性并发症。我们假设，肺部早期宿主与病原体的相互作用决定了金黄色葡萄球菌是成功感染还是被天然防御系统消除。对肺炎的发病机制，特别是最初的微生物：宿主的认识有限 互动。利用最先进的活体模型系统和基因组/蛋白质组技术，我们将研究细菌进入肺部后最初几个小时内的早期微生物和宿主反应。四个目标将解决我们的假设。在目标1中，我们将使用基因组阵列分析来表征细菌基因表达的变化，以响应感染的最初几个小时的肺部环境。目标2将检测与细菌表面结合的呼吸道液体中的宿主蛋白，并将这些与目标1中观察到的同一时间框架内检测的基因表达的变化相关联。此外，我们还将对小鼠呼吸道液体蛋白质组进行表征，这一特征尚未确定。这些研究可以确定在感染的初始阶段向生物体发出信号的宿主蛋白，并进一步确定哪些蛋白是宿主对感染的先天防御。目的3利用TLR表达缺陷的动物，特别是表达下游信号分子MyD88的缺陷动物，确定TLR在金黄色葡萄球菌与宿主相互作用中的作用。这些研究将评估初始炎症反应对细菌生存和宿主免疫的重要性。最终目的将扩大上述实验，进一步检查细菌表面相关蛋白基因和反义基因抑制技术在我们的肺炎动物模型中的重要性，以确定那些主要参与呼吸道最初相互作用的基因及其产物。 这些研究将通过检查宿主的两侧：感染早期的病原体界面，对下呼吸道细菌的发病机制产生新的见解。这些见解可能对肺炎、急性肺损伤及其后遗症的发病机制有重要影响。

Staphylococcus aureus is the second leading cause of hospital-acquired pneumonia and an important agent of severe community-acquired pneumonia. Pneumonia is both an important preceding event to acute lung injury and the most commonly fatal complication of ARDS. We hypothesize that early host:pathogen interactions in the lung determine whether S. aureus establishes a successful infection or is eliminated by innate defenses. There is a limited understanding of the pathogenesis of pneumonia, especially the initial microbial:host interaction. Using state of the art in vivo model systems and genomic/proteomic technology we will investigate the early microbial and host responses in the first few hours after bacterial entry into the lungs. Four aims will address our hypothesis. In aim 1 we will characterize changes in bacterial gene expression using genomic array analysis in response to the lung environment during the first few hours of infection. Aim 2 will examine the host proteins in airway fluid, which bind to the bacterial surface and correlate these to changes in gene expression examined over the same time frame as observed in aim 1. In addition, we will characterize the mouse airway fluid proteome, which has yet to be characterized. These studies may identify the host proteins which serve as signals to the organism during the initial phases of infection and further define those which serve as innate defenses against infection for the host. Aim 3 will determine the role of Toll-Like Receptors (TLR) on the interaction of S. aureus with the host, using animals deficient in TLR expression; specifically defective for expressing the downstream signaling molecule MyD88. These studies will evaluate the importance of the initial inflammatory response to bacterial survival and host immunity. The final aim will extend the above experiments by further examining the importance of the bacterial surface associated protein genes with antisense gene inhibition technology in our animal model of pneumonia, to identify those genes and their products which are primarily involved in the initial interactions in the airway. These studies will yield novel insights into bacterial pathogenesis in the lower respiratory tract by examining both sides of the host:pathogen interface in the early stages of infection. These insights could have important implications for the mechanisms underlying the initiation of pneumonia, acute lung injury, and its sequelae.