Host Defense Against Intracellular Infection of the Lung

描述(申请人提供)：嗜肺军团菌是引起肺炎的原因 军团菌病与一种典型的肺泡内寄生虫 巨噬细胞。吸入性呼吸的初始识别途径 细菌可能在先天的激活中起着至关重要的作用。 防御和启动特定的适应性免疫。信令 介导下层嗜肺性乳杆菌早期反应的受体 呼吸道和这种生物颠覆病毒的机制 对感染的防御性反应知之甚少。Toll样受体有 作为一类重要的模式识别分子出现，它可以 启动细胞对各种微生物刺激的激活反应。 Toll样受体在介导肺泡巨噬细胞反应中的作用 感染和在激活肺内的抗菌防御机制尚不清楚。 强毒嗜肺乳杆菌能够钝化肺泡细胞因子反应 巨噬细胞通过未阐明的机制依赖于 特定的细菌基因。这项提案的总体目标是确定 刺激细胞内天然防御的识别途径 细菌，并探索毒力生物颠覆宿主的机制 抵抗。具体目标如下： 1.确定Toll样受体(TLRs)在细胞调节中的作用 对嗜肺乳杆菌(Lp)的反应。这个目标将检验这样一个假设，即TLRs， 单独或联合调节肺泡的初始激活 巨噬细胞对脂蛋白的反应，起到防御细胞内的作用 感染。 2.确定TLRs在肺宿主体内防御LP中的作用。 这一目标将检验这样的假设，即通过TLRs传递信号有助于刺激 对LP的先天防御，控制早期细菌清除和 启动适应性反应。 3.确定强毒嗜肺性乳杆菌颠覆 肺泡巨噬细胞的激活反应。这一目标将检验这一假设 细菌DOT/ICM基因引导巨噬细胞摄取嗜肺乳杆菌 在比较细菌中导致细胞活性减弱的途径 缺乏这些基因座。

DESCRIPTION (provided by applicant): Legionella pneumophila is the cause of Legionnaires' Disease and a prototypical intracellular parasite of alveolar macrophages. The pathways involved in the initial recognition of inhaled bacteria are likely to be critically important in the activation of innate defenses and the initiation of specific adaptive immunity. The signaling receptors that mediate early responses to L. pneumophila in the lower respiratory tract and the mechanisms by which this organism subverts the defensive response to infection are poorly understood. Toll-like receptors have emerged as an important family of pattern recognition molecules that can initiate cellular activation responses to a wide variety of microbial stimuli. The roles of Toll-like receptors in mediating alveolar macrophage responses to infection and in activating pulmonary anti-bacterial defenses are unknown. Virulent L. pneumophila is able to blunt the cytokine response of alveolar macrophages by unelucidated mechanisms that are dependent on the expression of specific bacterial genes. The overall goals of this proposal are to determine the recognition pathways that stimulate innate defenses to intracellular bacteria, and to explore mechanisms by which virulent organisms subvert host resistance. The specific aims are as follows: 1. Determine the roles of Toll-like receptors (TLRs) in mediating cellular responses to L. pneumophila (Lp). This aim will test the hypothesis that TLRs, singly or in combination, mediate the initial activation of alveolar macrophages in response to Lp, serving to defend the cell against intracellular infection. 2. Determine the roles of TLRS in pulmonary host defense against Lp in vivo. This aim will test the hypothesis that signaling via TLRs serves to stimulate innate defenses against Lp that control early bacterial clearance and initiation of the adaptive response. 3. Define the mechanisms by which virulent L. pneumophila subverts the activation response of alveolar macrophages. This aim will test the hypothesis that bacterial dot/icm genes direct macrophage uptake of L. pneumophila by a pathway that results in diminished cellular activation in comparison bacteria deficient in these loci.