Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infecion in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in Irgm1 -/- mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses. Overall design: To elucidate the role of immunity-related GTPase family M member 1 (IRGM1) in Mycobacterium tuberculosis (Mtb) infection using a murine model. Wild-type (WT) and IRGM1-deficient (Irgm1-/-) mice were infected with Mtb via aerosol route, ensuring an inoculum of 150-200 colony-forming units (CFU). Lungs were harvested 21 days post-infection (dpi) to assess the impact of IRGM1 on the host response to Mtb infection.For bulk RNA sequencing (RNA-seq), total RNA was isolated from the lungs under the following experimental conditions: Irgm1-/- naïve (uninfected control), WT naïve (uninfected control), Irgm1-/- at 21 dpi (infected), WT at 21 dpi (infected).