THE ROLE OF ESCRT IN MACROPHAGE RESISTANCE TO MYCOBACTERIA

ESCRT 在巨噬细胞抵抗分枝杆菌中的作用

• 批准号: 9125720
• 负责人: JENNIFER A PHILIPS
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-01-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125720
• 关键词: Accounting; Alleles; Bacteria; Bacterial Infections; Binding; Bone Marrow; Cells; Complex; Data; Development; Drosophila genus; Early Endosome; Environment; Epidemic; Exhibits; Face; Genus Mycobacterium; Goals; Growth; Homologous Gene; Host Defense; Human; Infection; Interferons; Latex Bead; Light; Molecular; Mus; Mycobacterium bovis; Mycobacterium marinum; Mycobacterium smegmatis; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathway interactions; Phagolysosome; Phagosomes; Phenotype; Play; Population; Positioning Attribute; Predisposition; Proliferating; Protein-Protein Interaction Map; Proteins; Proteome; Proteomics; RNA interference screen; Resistance; Role; Sorting - Cell Movement; Staphylococcus aureus; System; Testing; Tuberculosis; Vacuole; World Health Organization; antimicrobial; base; burden of illness; functional genomics; genome-wide; hepatocyte growth factor-regulated tyrosine kinase substrate; improved; insight; killings; macrophage; microbicide; mutant; mycobacterial; novel; novel therapeutics; pathogen; prevent; protein complex; protein transport; research study; success; trafficking

DESCRIPTION (provided by applicant): Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (M.tb), and the World Health Organization estimates that in 2007 there were 9.27 million new cases and more than 1.7 million people died of tuberculosis. M.tb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. One way in which it does this is to convert the normally hostile environment of a macrophage into a niche in which it can effectively replicate. Normally during phagosome maturation, the bacterial vacuole is transformed from a comparatively inert compartment to a phagolysosome, an effective microbicidal and degradative compartment. However, a variety of mycobacterial species prevent the normal maturation of the phagosome, residing in a replicative niche that resembles an early endosome, although exactly how they do this is not clear. We hypothesize that to promote its intracellular survival M.tb secrete EsxH in order to inhibit the endosomal sorting complex required for transport (ESCRT), cellular machinery of the macrophage involved in protein trafficking. We found that the ESCRT machinery represents a major vulnerability of the cell, as it is required to control growth of non-pathogens, like Mycobacterium smegmatis, as well as of M.tb. Moreover, we identified a novel host-pathogen interaction between the M.tb protein, EsxH, and the host protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), which is a component of the ESCRT machinery. In this proposal, we seek to extend our preliminary studies in order to characterize the mechanism by which ESCRT protects against bacterial infection. In addition, we will investigate the interaction between EsxH and Hgs and evaluate its importance to the outcome of infection. These studies will provide important insight into how M.tb subverts the normal anti-microbial capacity of macrophages. If we understood how M.tb does this, we might be able to improve the mycobacterial killing capacity of the infected macrophage, enabling development of novel therapeutics that have the potential to significantly shorten therapy and change the face of the global epidemic.

描述（由申请人提供）：大约三分之一的世界人口感染了结核分枝杆菌（M.TB），世界卫生组织估计，2007年，有927万例新病例，有170万人死于结核病。 M.TB能够通过颠覆宿主的先天和适应性防御能力来确定这一巨大的疾病负担。这样做的一种方法是将巨噬细胞的正常敌对环境转换为可以有效复制的利基市场。通常在吞噬体成熟期间，细菌液泡从相对惰性室转变为吞噬体，有效的微生物和降解室。然而，多种分枝杆菌物种可以防止吞噬体的正常成熟，居住在类似于早期内体的复制生态位，尽管尚不清楚它们的工作原理。我们假设，为了促进其细胞内存活率M.TB分泌ESXH，以抑制运输所需的内体分类复合物（ESCRT），即参与蛋白质运输的巨噬细胞的细胞机械。我们发现，ESCRT机械代表了该细胞的主要脆弱性，因为它需要控制非path菌的生长，例如Smegmatis以及M.TB。此外，我们确定了M.TB蛋白，ESXH和宿主蛋白肝细胞生长因子调节的酪氨酸激酶底物（HGS/HRS）之间的新型宿主 - 病原体相互作用，这是ESCRT机械的组成部分。在此提案中，我们试图扩展我们的初步研究，以表征ESCRT预防细菌感染的机制。此外，我们将研究ESXH和HGS之间的相互作用，并评估其对感染结果的重要性。这些研究将为M.TB如何颠覆巨噬细胞的正常抗微生物能力提供重要的见解。如果我们了解M.TB是如何做到这一点的，那么我们也许能够提高感染巨噬细胞的分枝杆菌杀戮能力，从而使新型治疗剂的发展有可能显着缩短治疗并改变全球流行病的面貌。