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    Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation

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    Type
    Article
    Authors
    Abdallah, Abdallah
    Bestebroer, Jovanka
    Savage, Nigel D L
    De Punder, Karin
    Van Zon, Maaike
    Wilson, Louis D.
    Korbee, Cees J.
    van der Sar, Astrid M.
    Ottenhoff, Tom Hm M
    Van Der Wel, Nicole N.
    Bitter, Wilbert M.
    Peters, Peter J.
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Computational Bioscience Research Center (CBRC)
    Date
    2011-09-28
    Online Publication Date
    2011-09-28
    Print Publication Date
    2011-11-01
    Permanent link to this record
    http://hdl.handle.net/10754/561882
    
    Metadata
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    Abstract
    During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5 - two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators - during the macrophage infection cycle. Using wild-type, ESX-1- and ESX-5-deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1b activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread. Copyright © 2011 by The American Association of Immunologists, Inc.
    Citation
    Abdallah, A. M., Bestebroer, J., Savage, N. D. L., de Punder, K., van Zon, M., Wilson, L., … Peters, P. J. (2011). Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation. The Journal of Immunology, 187(9), 4744–4753. doi:10.4049/jimmunol.1101457
    Publisher
    The American Association of Immunologists
    Journal
    The Journal of Immunology
    DOI
    10.4049/jimmunol.1101457
    PubMed ID
    21957139
    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.1101457
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC)

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