The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy
- PMID: 26048136
- PMCID: PMC4466081
- DOI: 10.1016/j.chom.2015.05.004
The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
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Comment in
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Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1.Cell Host Microbe. 2015 Jun 10;17(6):799-810. doi: 10.1016/j.chom.2015.05.003. Epub 2015 Jun 2. Cell Host Microbe. 2015. PMID: 26048138
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Mycobacterium tuberculosis Meets the Cytosol: The Role of cGAS in Anti-mycobacterial Immunity.Cell Host Microbe. 2015 Jun 10;17(6):733-5. doi: 10.1016/j.chom.2015.05.017. Cell Host Microbe. 2015. PMID: 26067600
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