Mycobacterium tuberculosis nuoG Is a virulence gene that inhibits apoptosis of infected host cells

Kamalakannan Velmurugan, Bing Chen, Jessica L. Miller, Sharon Azogue, Serdar Gurses, Tsungda Hsu, Michael Glickman, William R. Jacobs, Steven A. Porcelli, Volker Briken

Research output: Contribution to journalArticle

194 Scopus citations

Abstract

The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.

Original languageEnglish (US)
Pages (from-to)972-980
Number of pages9
JournalPLoS pathogens
Volume3
Issue number7
DOIs
StatePublished - Jul 2007

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Fingerprint Dive into the research topics of 'Mycobacterium tuberculosis nuoG Is a virulence gene that inhibits apoptosis of infected host cells'. Together they form a unique fingerprint.

  • Cite this