Host Defense Against Intracellular Infection of the Lung

描述（由申请方提供）：嗜肺军团菌是 军团病与肺泡上皮细胞内典型寄生虫 巨噬细胞参与吸入性疾病初始识别的途径 细菌可能在激活先天性 防御和特异性适应性免疫的启动。信令 介导对L.下肺嗜肺 呼吸道和机制，通过这种有机体颠覆了 对感染的防御反应知之甚少。Toll样受体具有 作为一个重要的模式识别分子家族出现， 启动对多种微生物刺激的细胞活化反应。 Toll样受体在介导肺泡巨噬细胞对抗氧化剂反应中的作用 感染和激活肺部抗菌防御的作用尚不清楚。 毒湖嗜肺菌能够减弱肺泡上皮细胞的细胞因子反应， 巨噬细胞通过依赖于表达的未阐明的机制， 特定的细菌基因本提案的总体目标是确定 刺激先天防御的识别途径， 细菌，并探索有毒生物破坏宿主的机制 阻力具体目标如下： 1.确定Toll样受体（TLR）在介导细胞凋亡中的作用。 对L的回应嗜肺菌（Lp）。这一目标将检验TLR， 单独或组合，介导肺泡的初始激活， 巨噬细胞响应Lp，用于防御细胞内 感染 2.确定TLRS在体内肺宿主防御Lp中的作用。 这一目标将检验通过TLR的信号传导用于刺激 对Lp的先天防御，控制早期细菌清除， 启动适应性反应。 3.定义致病性L。嗜肺菌颠覆了 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基因指导巨噬细胞摄取L.嗜肺菌 导致对比细菌中细胞活化减少的途径 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.