Modulation of apoptosis by Legionella Pneumophila

嗜肺军团菌对细胞凋亡的调节

• 批准号: 7313327
• 负责人: Yousef A Abu Kwaik
• 金额: $ 37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313327
• 关键词: Abbreviations; Adenylate Cyclase; Apoptosis; Apoptotic; Biochemical; Biogenesis; Biological Models; Biological Preservation; Biology; Caspase Inhibitor; Cell physiology; Cells; Cellular biology; Co-Immunoprecipitations; Disease; Early Endosome; Endoplasmic Reticulum; Ensure; Golgi Apparatus; Human; Infection; Knowledge; Lead; Legionella; Legionella pneumophila; Life Style; Light; Mediating; Molecular; Nuclear; Organism; Pan Genus; Pathway interactions; Peptides; Phagolysosome; Phagosomes; Prevention therapy; Process; Proteins; RNA Interference; Role; Small Interfering RNA; Staging; Testing; Type IV Secretion System Pathway; Vesicle; caspase-3; clinical application; disorder prevention; inhibitor/antagonist; macrophage; monocyte; mutant; novel; pathogen; programs; trafficking

DESCRIPTION (provided by applicant): Legionella pneumophila is an intracellular pathogen that evades endocytic fusion and hijacks ER-to-golgi vesicle traffic to remodel its phagosome into an ER-derived compartment permissive for intracellular replication. The Dot/lcm type IV secretion system of L. pneumophila is essential for both modulation of phagosome biogenesis and modulation of the macrophage apoptotic pathways through robust early and novel activation of caspase-3, independent of the intrinsic and extrinsic pathways of apoptosis. The Dot/lcm- mediated activation of caspase-3 results in cleavage of Rabaptin-5, which is an effector of the early endosome regulator Rab5. Inhibition of caspase-3 using caspase-3 peptide inhibitors blocks intracellular replication of L. pneumophila and results in trafficking of the organism to phagolysosomes, similar to dot/icm mutants. Our hypothesis is: Caspase-3-meditaed cleavage of Rabaptin-5 is central to the arrested biogenesis of the Legionella-containing phagosome (LCP) and to intracellular replication. To test this hypothesis, our specific aims are to examine the following: Specific aim I. Role of caspase-3 activation in biogenesis of the LCP; Specific aim II: Role of caspase-3-mediated cleavage of Rabaptin-5 in biogenesis of the LCP; Specific aim III. Identification of the L. pneumophila effector involved in caspase-3 activation. Significance: Our proposed studies are the crux of our understanding of the molecular and cellular mechanisms by which this pathogen commandeer the host cell, and will she light on the cellular mechanism by which this pathogen engages a cross talk between the apoptotic pathways and vesicle traffic in the host cell to remodel it to its liking. The bacterial effector involved in this process is a potential target for therapy and prevention of the disease.

描述（由申请人提供）：嗜肺军团菌是一种细胞内病原体，它逃避内吞融合并劫持内质网到高尔基体囊泡的运输，以将其吞噬体重塑为内质网衍生的区室，从而允许细胞内复制。嗜肺军团菌的 Dot/lcm IV 型分泌系统对于调节吞噬体生物发生和通过 caspase-3 的强大早期和新颖激活来调节巨噬细胞凋亡途径至关重要，独立于细胞凋亡的内在和外在途径。 Dot/lcm介导的caspase-3激活导致Rabaptin-5的裂解，Rabaptin-5是早期内体调节剂Rab5的效应子。使用 caspase-3 肽抑制剂抑制 caspase-3 可阻断嗜肺军团菌的细胞内复制，并导致生物体转运至吞噬溶酶体，类似于 dot/icm 突变体。我们的假设是：Caspase-3 介导的 Rabaptin-5 裂解对于含有军团菌的吞噬体 (LCP) 的生物发生的停滞和细胞内复制至关重要。为了检验这一假设，我们的具体目标是检查以下内容： 具体目标 I. caspase-3 激活在 LCP 生物发生中的作用；具体目标 II：caspase-3 介导的 Rabaptin-5 裂解在 LCP 生物发生中的作用；具体目标三．鉴定参与 caspase-3 激活的嗜肺军团菌效应子。意义：我们提出的研究是我们理解这种病原体控制宿主细胞的分子和细胞机制的关键，并将阐明这种病原体在细胞凋亡途径和囊泡运输之间进行交互作用的细胞机制。宿主细胞将其改造为自己喜欢的样子。参与该过程的细菌效应子是治疗和预防该疾病的潜在靶标。