Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

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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

Edité par CCSD ; Elsevier Inc -

Supplemental Information can be found online at https://doi.org/10.1016/j.celrep.2019.04.110. International audience. 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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