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The Role of ESX-1 in Pathogenesis

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  • Author: Ka-Wing Wong1
  • Editors: William R. Jacobs Jr.2, Helen McShane3, Valerie Mizrahi4, Ian M. Orme5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, People’s Republic of China; 2: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 3: University of Oxford, Oxford OX3 7DQ, United Kingdom; 4: University of Cape Town, Rondebosch 7701, South Africa; 5: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec May 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0001-2015
  • Received 01 October 2015 Accepted 31 March 2017 Published 19 May 2017
  • Ka-Wing Wong, kwwong@gmail.com
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  • Abstract:

    In this article, we have described several cellular pathological effects caused by the ESX-1. The effects include induction of necrosis, NOD2 signaling, type I interferon production, and autophagy. We then attempted to suggest that these pathological effects are mediated by the cytosolic access of -derived materials as a result of the phagosome-disrupting activity of the major ESX-1 substrate ESAT-6. Such activity of ESAT-6 is most likely due to its pore-forming activity at the membrane. The amyloidogenic characteristic of ESAT-6 is reviewed here as a potential mechanism of membrane pore formation. In addition to ESAT-6, the ESX-1 substrate EspB interferes with membrane-mediated innate immune mechanisms such as efferocytosis and autophagy, most likely through its ability to bind phospholipids. Overall, the ESX-1 secretion system appears to be a specialized system for the deployment of host membrane-targeting proteins, whose primary function is to interrupt key steps in innate immune mechanisms against pathogens. Inhibitors that block the ESX-1 system or block host factors critical for ESX-1 toxicity have been identified and should represent attractive potential new antituberculosis drugs.

  • Citation: Wong K. 2017. The Role of ESX-1 in Pathogenesis. Microbiol Spectrum 5(3):TBTB2-0001-2015. doi:10.1128/microbiolspec.TBTB2-0001-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.TBTB2-0001-2015
2017-05-19
2017-09-21

Abstract:

In this article, we have described several cellular pathological effects caused by the ESX-1. The effects include induction of necrosis, NOD2 signaling, type I interferon production, and autophagy. We then attempted to suggest that these pathological effects are mediated by the cytosolic access of -derived materials as a result of the phagosome-disrupting activity of the major ESX-1 substrate ESAT-6. Such activity of ESAT-6 is most likely due to its pore-forming activity at the membrane. The amyloidogenic characteristic of ESAT-6 is reviewed here as a potential mechanism of membrane pore formation. In addition to ESAT-6, the ESX-1 substrate EspB interferes with membrane-mediated innate immune mechanisms such as efferocytosis and autophagy, most likely through its ability to bind phospholipids. Overall, the ESX-1 secretion system appears to be a specialized system for the deployment of host membrane-targeting proteins, whose primary function is to interrupt key steps in innate immune mechanisms against pathogens. Inhibitors that block the ESX-1 system or block host factors critical for ESX-1 toxicity have been identified and should represent attractive potential new antituberculosis drugs.

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