Elucidating the Biogenesis of the Yersinia pestis Containing Vacuole

阐明含有液泡的鼠疫耶尔森氏菌的生物发生

基本信息

批准号：
9233902
负责人：
Matthew B Lawrenz
金额：
$ 18.84万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233902
关键词：
AGFG1 gene Acute Autophagocytosis Autophagosome Bacteria Biogenesis Bubonic Plague Cells Comprehension Confocal Microscopy Data Development Disease Electron Microscopy Exclusion Generations Goals Growth Guanosine Triphosphate Phosphohydrolases Immune Evasion Individual Infection Integration Host Factors Lysosomes Mediating Mediator of activation protein Membrane Molecular Organelles Pathogenesis Phagocytosis Phagolysosome Phagosomes Plague Play Process Proteins RNA Interference Recombinant Proteins Recruitment Activity Role Testing Transmission Electron Microscopy Vacuole Virulence Virulence Factors Work Yersinia Yersinia pestis base combat defined contribution design human disease improved killings knock-down macrophage novel therapeutic intervention novel vaccines pathogen public health relevance rab GTP-Binding Proteins trafficking

项目摘要

DESCRIPTION (provided by applicant): Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. Growing evidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Upon phagocytosis, Y. pestis alters the maturation of the phagosome to generate a protective compartment within the cell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibition of YCV acidification, expansion into a spacious vacuole, and acquisition of the autophagic markers. However, the mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate the YCV have not been defined. Recently we have identified a subset of host Rab GTPases that are required for Y. pestis to survive within macrophages. Because Rab proteins are key mediators of vesicular trafficking, phagosome maturation, and autophagy, we hypothesize that these GTPases are required by Y. pestis to subvert phagosome maturation and generate the YCV, thus protecting the bacterium from macrophage clearance. As Rab proteins mediate many aspects of vesicular trafficking through direct interactions with specific organelles and recruitment of effector proteins, in Aim 1 we will determine if Rab GTPase required for Y. pestis intracellular survival are specifically recruited to the YCV. In Aim 2, we will determine the contribution of individual Rab proteins on the biogenesis of the YCV. These studies will be the first to define the contribution of host Rab GTPases to the formation of the YCV. Ultimately, understanding the YCV biogenesis process will enable us to identify Y. pestis pathogenicity factors that contribute to intracellular survival.

描述（由申请人提供）：鼠疫耶尔森氏菌是一种兼性细胞内病原体，可引起鼠疫疾病。越来越多的证据表明，巨噬细胞的细胞内生长对于鼠疫耶尔森氏菌的毒力很重要。鼠疫耶尔森氏菌会改变吞噬体的成熟。在细胞内产生一个称为含有耶尔森氏菌的真空 (YCV) 的保护室 YCV 产生的关键步骤包括抑制。然而，细菌用于破坏正常吞噬体成熟过程并产生 YCV 的机制最近尚未确定。鼠疫耶尔森氏菌在巨噬细胞内生存所需的 GTP 酶由于 Rab 蛋白是囊泡运输、吞噬体成熟和自噬的关键介质，因此我们发现这些酶。鼠疫耶尔森氏菌需要 GTP 酶来破坏吞噬体成熟并产生 YCV，从而保护细菌免遭巨噬细胞清除，因为 Rab 蛋白通过与特定细胞器的直接相互作用和效应蛋白的募集来介导囊泡运输的许多方面，因此在目标 1 中，我们将。确定鼠疫耶尔森氏菌细胞内存活所需的 Rab GTP 酶是否被特异性招募至 YCV 在目标 2 中，我们将确定单个 Rab 蛋白对 YCV 的贡献。这些研究将首次明确宿主 Rab GTP 酶对 YCV 形成的贡献，最终，了解 YCV 生物发生过程将使我们能够识别有助于细胞内存活的鼠疫杆菌致病因子。