Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity
2019
Benmerzoug, Sulayman | Bounab, Badreddine | Rose, Stéphanie | Gosset, David | Biet, Franck | Cochard, Thierry | Xavier, Aurore | Rouxel, Nathalie | Fauconnier, Louis | Horsnell, William G C | Ryffel, Bernhard | Togbe, Dieudonnée | Quesniaux, Valérie | Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM) ; Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS) | Centre de biophysique moléculaire (CBM) ; Université d'Orléans (UO)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Infectiologie et Santé Publique (UMR ISP) ; Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT) | Artimmune ; privé | Institute of Infectious Diseases and Molecular Medicine (IDM) ; University of Cape Town | Institute of Microbiology and Infection ; University of Birmingham [Birmingham] | LE STUDIUM Loire Valley Institute for Advanced Studies (LE STUDIUM) ; Bureau de Recherches Géologiques et Minières (BRGM)-Institut National de la Recherche Agronomique (INRA)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de recherche pour le développement [IRD] : UR-Centre National de la Recherche Scientifique (CNRS) | Immunologie et Embryologie Moléculaires (IEM) ; Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS) | National Center for Scientific Research (CNRS) ; University of Orléans ; European funding in Région Centre-Valde Loire (FEDER no. 2016-00110366 and EX0057560)
Supplemental Information can be found online at https://doi.org/10.1016/j.celrep.2019.04.110
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Show more [+] Less [-]English. Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.
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