Mechanism of M. tuberculosis Phagosome Maturation Arrest

结核分枝杆菌吞噬体成熟停滞的机制

• 批准号: 7284512
• 负责人: VOJO P DERETIC
• 金额: $ 4.41万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284512
• 关键词: Mycobacterium tuberculosis; bacteria infection mechanism; bacterial cytopathogenic effect; cell fusion; cell growth regulation; cellular immunity; clinical research; genetic strain; guanosinetriphosphatases; host organism interaction; laboratory mouse; macrophage; membrane activity; phagocytosis; phosphatidylinositol 3 kinase; receptor mediated endocytosis; transfection; vesicle /vacuole

DESCRIPTION (provided by applicant): The ability of Mycobacterium tuberculosis to infect an extraordinary number of people, combined with the widespread emergence of multidrug resistance and opportunistic infections in AIDS, has lead to its placement on the NIAID list of biodefense and emerging infectious agents. M. tuberculosis persistence in human populations rests upon its ability to infect and survive in macrophages. Intracellular M. tuberculosis inhibits phagosomal maturation and resides in a pathogen-friendly phagosome escaping lysosomal bactericidal mechanisms and efficient antigen presentation. The long-term objectives of this project are to characterize mycobacterial products responsible for the M. tuberculosis phagosomal maturation block and identify the host cell membrane trafficking processes that are targeted by the mycobacterial factors. These phenomena have been linked to mycobacterial interference with membrane trafficking and organelle biogenesis processes controlled by host cell Rab GTPases. We hypothesize that M. tuberculosis interferes with specific Rab-interacting partners, including a Rab effector, phosphatidylinositol 3-kinase, that prepares phagosomes for tethering and fusion with other organelles. An integral part of this hypothesis is that M. tuberculosis lipids, which mimic mammalian phosphatidylinositols, affect organellar fusion and phagosomal maturation by interfering with phosphatidylinositol 3-kinase-dependent processes in the host cell. The specific aims are: 1. Identify M. tuberculosis lipid and protein products affecting phagosome maturation and characterize their mode of action. 2. Delineate the role of host cell membrane trafficking regulators including Rab5 effectors in M. tuberculosis phagosome maturation arrest. 3. Characterize novel, cell biology-based processes that can counteract M. tuberculosis phagosome maturation arrest. This three-prong approach will improve our understanding of a marquee pathogenic determinant of M. tuberculosis and provide a foundation for new interventions potentially combating both active disease and latent infection.

描述（由申请人提供）：结核分枝杆菌感染大量人群的能力，加上艾滋病中广泛出现的多重耐药性和机会性感染，使其被列入 NIAID 生物防御和新兴感染原清单。结核分枝杆菌在人群中的持久性取决于其感染巨噬细胞并在巨噬细胞中存活的能力。细胞内结核分枝杆菌抑制吞噬体成熟，并驻留在病原体友好的吞噬体中，逃避溶酶体杀菌机制和有效的抗原呈递。该项目的长期目标是表征负责结核分枝杆菌吞噬体成熟阻断的分枝杆菌产物，并确定分枝杆菌因子靶向的宿主细胞膜运输过程。这些现象与分枝杆菌干扰宿主细胞 Rab GTP 酶控制的膜运输和细胞器生物发生过程有关。我们假设结核分枝杆菌干扰特定的 Rab 相互作用伙伴，包括 Rab 效应子、磷脂酰肌醇 3-激酶，它为吞噬体与其他细胞器的束缚和融合做好准备。该假说的一个组成部分是，结核分枝杆菌脂质模仿哺乳动物磷脂酰肌醇，通过干扰宿主细胞中磷脂酰肌醇3激酶依赖性过程来影响细胞器融合和吞噬体成熟。具体目标是： 1. 鉴定影响吞噬体成熟的结核分枝杆菌脂质和蛋白质产物并表征其作用模式。 2. 描述宿主细胞膜运输调节因子（包括 Rab5 效应子）在结核分枝杆菌吞噬体成熟停滞中的作用。 3. 描述基于细胞生物学的新颖过程，可以抵消结核分枝杆菌吞噬体成熟停滞。这种三管齐下的方法将提高我们对结核分枝杆菌重要致病决定因素的理解，并为可能对抗活动性疾病和潜伏感染的新干预措施奠定基础。