UMMS Affiliation

Department of Microbiology and Physiological Systems; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine

Date

3-31-2011

Document Type

Article

Subjects

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

Disciplines

Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences | Microbiology

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.

Comments

Citation: 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

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.

Related Resources

Link to Article in PubMed

Journal Title

PloS one

PubMed ID

21483832

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.