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

Abstract

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.\xa0tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M.\xa0tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M.\xa0tuberculosis 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\xa0silica-induced exacerbation of M.\xa0tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M.\xa0tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M.\xa0tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the\xa0host response to pathogens such as M.\xa0tuberculosis.