Early host microbial interactions in S. aureus pneumonia

金黄色葡萄球菌肺炎的早期宿主微生物相互作用

• 批准号: 6820113
• 负责人: CRAIG E. RUBENS
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820113
• 关键词: Staphylococcus aureus; bacteria infection mechanism; bacterial genetics; bacterial pneumonia; functional /structural genomics; gene expression; host organism interaction; laboratory mouse; microarray technology; proteomics; toll like receptor

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.

金黄色葡萄球菌是医院获得性肺炎的第二大病因，也是严重社区获得性肺炎的重要病原体。肺炎是急性肺损伤的重要前驱事件，也是ARDS最常见的致命并发症。我们推测早期宿主与病原体在肺部的相互作用决定了S.金黄色葡萄球菌建立成功的感染或被先天防御所消除。人们对肺炎发病机制的了解有限，尤其是最初的微生物：宿主 互动使用最先进的体内模型系统和基因组/蛋白质组学技术，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，以响应在感染的最初几个小时内的肺部环境。目标2将检测气道液中的宿主蛋白质，这些蛋白质与细菌表面结合，并将这些蛋白质与目标1中观察到的相同时间范围内检测的基因表达变化相关联。此外，我们将表征小鼠气道液蛋白质组，这还有待于表征。这些研究可以鉴定在感染的初始阶段作为生物体信号的宿主蛋白，并进一步确定那些作为宿主对感染的先天防御的蛋白。目的3探讨Toll样受体（TLR）在S.金黄色葡萄球菌与宿主，使用TLR表达缺陷的动物;特别是表达下游信号分子MyD 88缺陷的动物。这些研究将评估初始炎症反应对细菌存活和宿主免疫的重要性。最终的目的是通过在我们的肺炎动物模型中使用反义基因抑制技术进一步检查细菌表面相关蛋白基因的重要性来扩展上述实验，以鉴定主要参与气道中初始相互作用的那些基因及其产物。 这些研究将产生新的见解，在下呼吸道细菌的发病机制，通过检查双方的主机：病原体界面在感染的早期阶段。这些见解可能对肺炎、急性肺损伤及其后遗症的发病机制具有重要意义。