Cell Host & Microbe
Volume 17, Issue 6, 10 June 2015, Pages 811-819
Journal home page for Cell Host & Microbe

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

https://doi.org/10.1016/j.chom.2015.05.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • cGAS is essential for type I IFN production during M. tuberculosis infection

  • cGAS activation targets M. tuberculosis to the selective autophagy pathway

  • cGAS deficiency leads to increased intracellular M. tuberculosis growth

  • cGAS directly binds to M. tuberculosis genomic DNA during infection

Summary

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.

Cited by (0)

6

Present address: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA

7

Co-first author