Show simple item record

dc.contributor.authorLee, Jinhee
dc.contributor.authorRepasy, Teresa
dc.contributor.authorPapavinasasundaram, Kadamba
dc.contributor.authorSassetti, Christopher M.
dc.contributor.authorKornfeld, Hardy
dc.date2022-08-11T08:09:40.000
dc.date.accessioned2022-08-23T16:39:49Z
dc.date.available2022-08-23T16:39:49Z
dc.date.issued2011-03-31
dc.date.submitted2012-09-06
dc.identifier.citationLee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H (2011) <em>Mycobacterium tuberculosis</em> Induces an Atypical Cell Death Mode to Escape from Infected Macrophages. PLoS ONE 6(3): e18367. doi:10.1371/journal.pone.0018367. <a href="http://dx.doi.org/10.1371/journal.pone.0018367" target="_blank">Link to article on publisher's site</a>
dc.identifier.issn1932-6203 (Linking)
dc.identifier.doi10.1371/journal.pone.0018367
dc.identifier.pmid21483832
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39552
dc.description.abstractBACKGROUND: 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=21483832&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>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.</p>
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectCathepsins
dc.subjectCells, Cultured
dc.subjectChromatography, High Pressure Liquid
dc.subjectHomeodomain Proteins
dc.subjectHydrogen-Ion Concentration
dc.subjectMacrophages
dc.subjectMembrane Potential, Mitochondrial
dc.subjectMice
dc.subjectMicroscopy, Electron, Scanning
dc.subjectMicroscopy, Electron, Transmission
dc.subjectMycobacterium tuberculosis
dc.subjectNecrosis
dc.subjectProto-Oncogene Proteins
dc.subjectTranscription Factors
dc.subjectVirulence
dc.subjectbcl-2 Homologous Antagonist-Killer Protein
dc.subjectbcl-2-Associated X Protein
dc.subjectImmunology and Infectious Disease
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.subjectMicrobiology
dc.titleMycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume6
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3348&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2348
dc.identifier.contextkey3299947
refterms.dateFOA2022-08-23T16:39:49Z
html.description.abstract<p>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.</p> <p>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.</p> <p>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.</p>
dc.identifier.submissionpathoapubs/2348
dc.contributor.departmentDepartment of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.source.pagese18367


Files in this item

Thumbnail
Name:
journal.pone.0018367.pdf
Size:
2.330Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record