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

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

Research output: Contribution to journalArticle

254 Scopus citations

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.

Original languageEnglish
Pages (from-to)811-819
Number of pages9
JournalCell Host and Microbe
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2015

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    Watson, R. O., Bell, S. L., MacDuff, D. A., Kimmey, J. M., Diner, E. J., Olivas, J., Vance, R. E., Stallings, C. L., Virgin, H. W., & Cox, J. S. (2015). The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy. Cell Host and Microbe, 17(6), 811-819. https://doi.org/10.1016/j.chom.2015.05.004