The Cytosolic Sensor cGAS Detects Mycobacterium Tuberculosis DNA to Induce Type I Interferons and Activate Autophagy

Cell Host Microbe. 2015 Jun 10;17(6):811-819. doi: 10.1016/j.chom.2015.05.004. Epub 2015 Jun 2.

Abstract

Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STING agonist, c-di-AMP. Upon sensing cytosolic DNA, cGAS also activates cell-intrinsic antibacterial defenses, promoting autophagic targeting of M. tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during infection, providing direct evidence that this unique host-pathogen interaction occurs in vivo. These data uncover a mechanism by which IFN is likely elicited during active human infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Bacterial / metabolism
  • Autophagy / physiology
  • Bacterial Proteins / metabolism
  • Cytosol / metabolism
  • DNA, Bacterial / metabolism*
  • Female
  • Host-Pathogen Interactions*
  • Interferon Type I / metabolism*
  • Legionella pneumophila / genetics
  • Legionella pneumophila / pathogenicity
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / pathogenicity
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Tuberculosis / microbiology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • DNA, Bacterial
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Interferon Type I
  • Nucleotidyltransferases
  • cGAS protein, mouse