Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages
UMass Chan Affiliations
Department of Medicine, Division of Pulmonary, Allergy and Critical Care MedicineDepartment of Microbiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2011-03-31Keywords
AnimalsApoptosis
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
Metadata
Show full item recordAbstract
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 siteDOI
10.1371/journal.pone.0018367Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39552PubMed ID
21483832Related Resources
Link to Article in PubMedRights
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