title: Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages.
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 ∼20 per macrophage but the precise nature of this demise has not been defined.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Lee
authors.forename: Teresa
authors.initials: T
authors.lastname: Repasy
authors.forename: Kadamba
authors.initials: K
authors.lastname: Papavinasasundaram
authors.forename: Christopher
authors.initials: C
authors.lastname: Sassetti
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D018398:Homeodomain Proteins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D009336:Necrosis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014774:Virulence; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C107475:Esx1 protein, mouse; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002403:Cathepsins