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

Autor: Naik SK; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., McNehlan ME; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Mreyoud Y; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Kinsella RL; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Smirnov A; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Chowdhury CS; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., McKee SR; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Dubey N; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Woodson R; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Kreamalmeyer D; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Stallings CL; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 05. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1101/2023.10.03.560720
Abstrakt: 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 infection 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 T H 1 immune responses.
Databáze: MEDLINE
Externí odkaz: