The Role of ESCRT in Macrophage Resistance to Mycobacteria

Summary

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

Top Publications

  1. ncbi Tuberculosis pathogenesis and immunity
    Jennifer 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
  2. pmc Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking
    Alka 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

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. Virulence Regulation by the Mycobacterium Tuberculosis Proteasome
    KATERINA HERAN DARWIN; Fiscal Year: 2013
  3. Molecular Analysis of Tuberculosis Immunity
    WILLIAM ROBERT JACOBS; Fiscal Year: 2013
  4. SLAM Gene Family Controlled Pathways to SLE
    CORNELIS P TERHORST; Fiscal Year: 2013
  5. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  6. Carbon monoxide resistance in Mycobacterium tuberculosis pathogenesis
    MICHAEL SHILOH; Fiscal Year: 2013
  7. Omics for TB Disease Progression (OTB)
    David R Sherman; Fiscal Year: 2013
  8. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
  9. GENETIC BASIS OF MYCOBACTERIAL INVASION
    Lalita Ramakrishnan; Fiscal Year: 2013
  10. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013

Detail Information

Publications3

  1. ncbi Tuberculosis pathogenesis and immunity
    Jennifer 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...
  2. pmc Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking
    Alka 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. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Virulence Regulation by the Mycobacterium Tuberculosis Proteasome
    KATERINA HERAN DARWIN; Fiscal Year: 2013
    ..We are working to characterize how the proteasome participates in these pathways, the knowledge of which may help us better understand the pathogenesis of one of the world's deadliest diseases. ..
  3. Molecular Analysis of Tuberculosis Immunity
    WILLIAM ROBERT JACOBS; Fiscal Year: 2013
    ..smegmatis ?ike mutant containing a set of M. tuberculosis genes (named IKEPLUS) elicits a bactericidal immunity against M. tuberculosis. Heterologous prime and boosts with ILEPLUS and attenuated M. tuberculosis will be explored. ..
  4. SLAM Gene Family Controlled Pathways to SLE
    CORNELIS P TERHORST; Fiscal Year: 2013
    ..Core A Genetic Mouse Core.PL: Ninghai Wang, Beth Israel Deaconess Medical. Center Core B Administrative Core.PL Cox Terhorst, Beth Israel Deaconess Medical Center. ..
  5. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  6. Carbon monoxide resistance in Mycobacterium tuberculosis pathogenesis
    MICHAEL SHILOH; Fiscal Year: 2013
    ..The proposed work will extend the current knowledge on M. tuberculosis's antimicrobial resistance mechanisms and reveal a novel microbial survival strategy. ..
  7. Omics for TB Disease Progression (OTB)
    David R Sherman; Fiscal Year: 2013
    ..This project combines separate advances in systems biology and network modeling to produce an experimentally grounded and verifiable systems-level model of the host regulatory networks that affect TB progression. ..
  8. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  9. GENETIC BASIS OF MYCOBACTERIAL INVASION
    Lalita Ramakrishnan; Fiscal Year: 2013
    ..By understanding these early interactions we hope to identify key steps for therapeutic intervention. ..
  10. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  11. Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal
    Marcelo B Sztein; Fiscal Year: 2013
    ..Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance. ..
  12. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  13. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  14. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  15. MOLECULAR GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS
    WILLIAM ROBERT JACOBS; Fiscal Year: 2013
    ..This invaluable tool will enable the elucidationof the molecular basis for this immune evasion, part of which we have found is mediated by a large gene cluster conserved within pathogenic Mycobacterial species. ..
  16. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  17. Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
    Liem Duy Nguyen; Fiscal Year: 2013
    ....
  18. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  19. Modulation of Host Responses by Mycobacterium Tuberculosis
    Jyothi Rengarajan; Fiscal Year: 2013
    ..Such proteins are attractive new drug targets for inhibition as they can potentially synergize with antibiotics and simultaneously enhance immune-mediated killing of Mtb. ..
  20. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..