IRG1 controls immunometabolic host response and restricts intracellular Mycobacterium tuberculosis infection

Here, we demonstrate that IRG1 is recruited to -containing phagosomes and that it influences the host response controlling infection. While IRG1 deficiency does not affect uptake of by macrophages and dendritic cells (DCs) , it increases the intracellular replication of . Concomitantly, in comparison to wild type cells, IRG1-deficient macrophages and DCs have increased levels of lipid droplets, a correlate of inflammation. These intracellular organelles store triacylglycerol and phospholipids that are hijacked by as reservoir of host nutrients. Exposure of IRG1-deficient mice to BCG via the intranasal route induced neither lethality nor severe lung immunopathology, while IRG1-deficient mice were highly susceptible to infection resulting in animal death three weeks post-infection linked to exacerbated inflammation and high mycobacterial burden. The lungs of infected IRG1-deficient mice displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Therefore, our findings demonstrate that IRG1 is a major player in controlling the acute phase of infection with a specific effect on pathogenic mycobacteria.