Genomes and Genes
The Role of ESCRT in Macrophage Resistance to Mycobacteria
Principal Investigator: Jennifer A Philips
Abstract: 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.
Funding Period: 2011-07-01 - 2016-06-30
more information: NIH RePORT
- Tuberculosis pathogenesis and immunityJennifer A Philips
Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA
Annu Rev Pathol 7:353-84. 2012..In addition, it highlights topics that need to be better understood to provide improved means of controlling TB worldwide...
- Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair traffickingAlka Mehra
Division of Infectious Diseases, Department of Medicine, Department of Pathology and Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
PLoS Pathog 9:e1003734. 2013..Further, EsxH, in complex with EsxG, disrupts ESCRT function and impairs phagosome maturation. Thus, we demonstrate a role for a TSSS and the host ESCRT machinery in one of the central features of tuberculosis pathogenesis. ..
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