title: 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.
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Watson
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Bell
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Donna A
authors.initials: DA
authors.lastname: MacDuff
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Kimmey
authors.affiliation: Department of Molecular & Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Elie J
authors.initials: EJ
authors.lastname: Diner
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Olivas
authors.affiliation: Department of Molecular & Cell Biology, University of California, Berkeley, California 94720, USA.|Howard Hughes Medical Institute, University of California, Berkeley, California 94720.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Stallings
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001343:Autophagy / Q000502:physiology; D001426:Bacterial Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000378:metabolism*; D016952:Legionella pneumophila / Q000235:genetics / Q000472:pathogenicity; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000382:microbiology; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D007370:Interferon Type I; D009713:Nucleotidyltransferases; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase