Pseudomonas aeruginosa-induced host cell pathogenesis

铜绿假单胞菌诱导的宿主细胞发病机制

• 批准号: 6583942
• 负责人: SASHA H SHAFIKHANI
• 金额: $ 4.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583942
• 关键词: Pseudomonas aeruginosa; apoptosis; bacteria infection mechanism; host organism interaction; laboratory mouse; molecular cloning; postdoctoral investigator

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (PA) is an opportunistic gram-negative pathogen responsible for a large number of nosocomial infections. Dr. Joanne Engel and her group have shown that PA103 induces apoptotic-like cell death in epithelial cells and macrophages by a Type III Secretion System (TTSS)-dependent mechanism. Consistent with the results of others, They have found this to be a Fas ligand- and Fas receptor-dependent process. We propose that PA-induced apoptosis occurs either by (A) direct translocation of a bacterial effector into the host cell (PAF, for Pseudomonas Apoptosis Factor) by the TTSS, resulting in activation of Fas-dependent apoptosis or by (B) direct induction of Fas-dependent apoptosis by one or more components of the type III translocation apparatus itself. We will identify the mechanism by which PAl03 induces TTS-dependent apoptotic-like cell death in eukaryotic cells. We will initially use genetic and proteomic approaches to identify a putative apoptosis-inducing type III secreted effector molecule. We may also test the alternative hypothesis that the TTSS itself is responsible for the induction of apoptosis by PA. We will express the PA TTSS in a Yersinia strain that lacks the plasmid encoded TTSS and test for restoration of apoptosis-inducing activity.

描述（由申请人提供）：铜绿假单胞菌（PA）是一种机会性革兰氏阴性病原体，导致大量医院感染。 Joanne Engel 博士和她的团队表明，PA103 通过 III 型分泌系统 (TTSS) 依赖性机制诱导上皮细胞和巨噬细胞发生细胞凋亡样细胞死亡。与其他人的结果一致，他们发现这是一个 Fas 配体和 Fas 受体依赖性过程。我们认为，PA 诱导的细胞凋亡可以通过以下两种方式发生：(A) 通过 TTSS 将细菌效应子直接易位至宿主细胞（PAF，假单胞菌凋亡因子），导致 Fas 依赖性细胞凋亡的激活；或者通过 (B) 直接诱导发生III 型易位装置本身的一种或多种成分引起的 Fas 依赖性细胞凋亡。我们将鉴定PAl03在真核细胞中诱导TTS依赖性细胞凋亡样细胞死亡的机制。我们将首先使用遗传和蛋白质组学方法来鉴定假定的诱导细胞凋亡的 III 型分泌效应分子。我们还可以检验另一种假设，即 TTSS 本身负责 PA 诱导细胞凋亡。我们将在缺乏编码 TTSS 的质粒的耶尔森氏菌菌株中表达 PA TTSS，并测试细胞凋亡诱导活性的恢复。