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（申请人提供）：世界上大约三分之一的人口感染结核分枝杆菌（M.tb），世界卫生组织估计，2007年有927万新发病例，170多万人死于结核病。结核分枝杆菌能够通过破坏宿主的先天性和适应性防御来建立这种巨大的全球性疾病负担。其中一种方法是将巨噬细胞通常的敌对环境转化为一个可以有效复制的小生境。通常在吞噬体成熟期间，细菌液泡从相对惰性的隔室转化为吞噬溶酶体，一种有效的杀微生物和降解隔室。然而，多种分枝杆菌物种阻止吞噬体的正常成熟，驻留在类似于早期内体的复制生态位中，尽管它们具体如何做到这一点尚不清楚。我们假设，为了促进其细胞内存活，结核分枝杆菌分泌EsxH，以抑制转运所需的内体分选复合物（ESCRT），参与蛋白质运输的巨噬细胞的细胞机制。我们发现ESCRT机制代表了细胞的主要脆弱性，因为它是控制非病原体如耻垢分枝杆菌以及结核分枝杆菌生长所必需的。此外，我们确定了一种新的宿主-病原体之间的相互作用的结核分枝杆菌蛋白质，EsxH，和宿主蛋白质肝细胞生长因子调节酪氨酸激酶底物（Hgs/Hrs），这是一个组成部分的ESCRT机器。在这个建议中，我们试图扩展我们的初步研究，以表征ESCRT保护免受细菌感染的机制。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。这些研究将为结核分枝杆菌如何破坏巨噬细胞的正常抗微生物能力提供重要的见解。如果我们了解结核分枝杆菌是如何做到这一点的，我们可能能够提高受感染巨噬细胞的分枝杆菌杀伤能力，从而开发出有可能显著缩短治疗时间并改变全球流行病面貌的新型疗法。