title: Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1.
abstract: Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Wassermann
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Sonia Garcia
authors.initials: SG
authors.lastname: Perin
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Ye
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; First Department of Internal Medicine, University of Cologne, 50937 Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rybniker
authors.affiliation: Institute for Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute for Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute for Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: stewart.cole@epfl.ch.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: andrea.ablasser@epfl.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ablasser
mesh_terms: D000818:Animals; D004269:DNA, Bacterial / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D014376:Tuberculosis / Q000382:microbiology*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004269:DNA, Bacterial; D007370:Interferon Type I; D009713:Nucleotidyltransferases; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse