The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy. Academic Article uri icon

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.

published proceedings

  • Cell Host Microbe

altmetric score

  • 7.5

author list (cited authors)

  • Watson, R. O., Bell, S. L., MacDuff, D. A., Kimmey, J. M., Diner, E. J., Olivas, J., ... Cox, J. S

citation count

  • 392

complete list of authors

  • Watson, Robert O||Bell, Samantha L||MacDuff, Donna A||Kimmey, Jacqueline M||Diner, Elie J||Olivas, Joanna||Vance, Russell E||Stallings, Christina L||Virgin, Herbert W||Cox, Jeffery S

publication date

  • June 2015