Host Defense Against Intracellular Infection of the Lung

宿主防御肺部细胞内感染

• 批准号: 6832185
• 负责人: Shawn J. Skerrett
• 金额: $ 26.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-10 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832185
• 关键词: Legionella; alveolar macrophages; bacterial genetics; biological signal transduction; cell line; clinical research; genetically modified animals; host organism interaction; human subject; intracellular parasitism; laboratory mouse; legionellosis; polymerase chain reaction; receptor expression; receptor mediated endocytosis; toll like receptor; transfection /expression vector; virulence; western blottings

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.

描述（由申请人提供）：肺炎军团菌是原因 军团疾病和肺泡的原型细胞内寄生虫 巨噬细胞。吸入初始识别的途径 细菌在激活先天可能至关重要 防御和特定自适应免疫的启动。信号传导 介导较低的肺炎乳杆菌的早期反应的受体 呼吸道和该生物颠覆的机制 对感染的防御反应知之甚少。 Toll样受体具有 成为一个重要的模式识别分子的家族，可以 引发对各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反应中的作用 感染和激活肺部抗细菌防御尚不清楚。 肺乳杆菌能够钝化肺泡的细胞因子反应 巨噬细胞通过取决于表达的无效机制 特定细菌基因。该提议的总体目标是确定 刺激先天防御对细胞内的识别途径 细菌，并探索有毒生物颠覆宿主的机制 反抗。具体目的如下： 1。确定Toll样受体（TLR）在介导细胞中的作用 对肺炎乳杆菌（LP）的反应。这个目标将检验以下假设，即TLR， 单独或组合，介导牙槽的初始激活 响应LP的巨噬细胞，用于防御细胞内 感染。 2。确定TLR在体内针对LP的肺部宿主防御中的作用。 此目的将检验以下假设，即通过TLRS发出信号来刺激 对控制早期细菌清除率和 自适应反应的启动。 3。定义了肺乳杆菌颠覆的机制 肺泡巨噬细胞的激活反应。这个目标将检验假设 那个细菌点/ICM基因直接通过A的肺乳杆菌吸收巨噬细胞 比较细菌会导致细胞活化减少的途径 这些基因座不足。