Interferon gamma regulates inflammation in a cell-extrinsic manner to control TB 4841

Abstract Description Incomplete understanding of the immune response to Mycobacterium tuberculosis (Mtb) hampers the development of effective vaccines and host-directed therapies for tuberculosis (TB), the leading cause of death from a single infectious agent. The central dogma in TB immunology is that interferon gamma (IFNγ) directly activates infected macrophages to kill intracellular Mtb. However, this simplistic model has repeatedly failed to explain outcomes in patients and in animal models. We recently observed that IFNγ is the primary regulator of Irg1 (ACOD1), an inhibitor of alternative (M2) macrophage activation, in lung monocyte-derived macrophages (MDMs) during Mtb infection. We also found that mice with IFNγ-deficient T cells share key features of TB lung pathology with Irg1-/- mice, including M2-skewed MDMs, elevated inflammatory cytokines, abundant granulocyte recruitment, and reduced disease tolerance. Quantitative confocal imaging and existing flow cytometry data in mixed bone marrow chimeric mice suggest another striking parallel: MDMs lacking either IFNγ receptor or IRG1 are similarly capable of restricting Mtb as wildtype MDMs in the same milieu in vivo. This challenges the central dogma by suggesting that cell-extrinsic immunomodulatory pathways govern IFNγ-dependent macrophage capacity to restrict Mtb in trans. We are now dissecting the relative roles of IRG1 and of neutrophil/ eosinophil control to address the fundamental question of how IFNγ mediates immunity against Mtb. Funding Sources Supported by National Institutes of Health Grants U19AI135976 (to K.B.U.), 75N93019C00070 (to K.B.U.), T32AI007044 (to K.M.), and 5K08AI166072 (to B.H.G.); Firland Foundation Grant 20230026C (to K.M.); American Lung Association Grant CAALA2023 (to K.M.); and NIH-funded Seattle TB Research Advancement Center (SEATRAC) Grant 1P30AI168034-01 (to K.M.). Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)