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    Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages

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    Authors
    Lee, Jinhee
    Repasy, Teresa
    Papavinasasundaram, Kadamba
    Sassetti, Christopher M.
    Kornfeld, Hardy
    UMass Chan Affiliations
    Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
    Department of Microbiology and Physiological Systems
    Document Type
    Journal Article
    Publication Date
    2011-03-31
    Keywords
    Animals
    Apoptosis
    Cathepsins
    Cells, Cultured
    Chromatography, High Pressure Liquid
    Homeodomain Proteins
    Hydrogen-Ion Concentration
    Macrophages
    Membrane Potential, Mitochondrial
    Mice
    Microscopy, Electron, Scanning
    Microscopy, Electron, Transmission
    Mycobacterium tuberculosis
    Necrosis
    Proto-Oncogene Proteins
    Transcription Factors
    Virulence
    bcl-2 Homologous Antagonist-Killer Protein
    bcl-2-Associated X Protein
    Immunology and Infectious Disease
    Life Sciences
    Medicine and Health Sciences
    Microbiology
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    Abstract
    BACKGROUND: Macrophage cell death following infection with Mycobacterium tuberculosis plays a central role in tuberculosis disease pathogenesis. Certain attenuated strains induce extrinsic apoptosis of infected macrophages but virulent strains of M. tuberculosis suppress this host response. We previously reported that virulent M. tuberculosis induces cell death when bacillary load exceeds approximately 20 per macrophage but the precise nature of this demise has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the characteristics of cell death in primary murine macrophages challenged with virulent or attenuated M. tuberculosis complex strains. We report that high intracellular bacillary burden causes rapid and primarily necrotic death via lysosomal permeabilization, releasing hydrolases that promote Bax/Bak-independent mitochondrial damage and necrosis. Cell death was independent of cathepsins B or L and notable for ultrastructural evidence of damage to lipid bilayers throughout host cells with depletion of several host phospholipid species. These events require viable bacteria that can respond to intracellular cues via the PhoPR sensor kinase system but are independent of the ESX1 system. CONCLUSIONS/SIGNIFICANCE: Cell death caused by virulent M. tuberculosis is distinct from classical apoptosis, pyroptosis or pyronecrosis. Mycobacterial genes essential for cytotoxicity are regulated by the PhoPR two-component system. This atypical death mode provides a mechanism for viable bacilli to exit host macrophages for spreading infection and the eventual transition to extracellular persistence that characterizes advanced pulmonary tuberculosis.
    Source
    Lee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H (2011) Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages. PLoS ONE 6(3): e18367. doi:10.1371/journal.pone.0018367. Link to article on publisher's site
    DOI
    10.1371/journal.pone.0018367
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39552
    PubMed ID
    21483832
    Related Resources
    Link to Article in PubMed
    Rights

    Copyright: © 2011 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    10.1371/journal.pone.0018367
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