Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses

The type I interferon (IFN) response is the major host arsenal against invading viruses. IRGM is a negative regulator of IFN responses under basal conditions. However, the role of human IRGM during viral infection has remained unclear. In this study, we show that IRGM expression is increased upon viral infection. IFN responses induced by viral PAMPs are negatively regulated by IRGM. Conversely, IRGM depletion results in a robust induction of key viral restriction factors including IFITMs, APOBECs, SAMHD1, tetherin, viperin, and HERC5/6. Additionally, antiviral processes such as MHC-I antigen presentation and stress granule signaling are enhanced in IRGM-deficient cells, indicating a robust cell-intrinsic antiviral immune state. Consistently, IRGM-depleted cells are resistant to the infection with seven viruses from five different families, including Togaviridae , Herpesviridae , Flaviviverdae , Rhabdoviridae , and Coronaviridae . Moreover, we show that Irgm1 knockout mice are highly resistant to chikungunya virus (CHIKV) infection. Altogether, our work highlights IRGM as a broad therapeutic target to promote defense against a large number of human viruses, including SARS-CoV-2, CHIKV, and Zika virus. Synopsis Depletion of Immunity Related GTPase M (IRGM) results in the upregulation of several key viral restriction factors. IRGM deficient cells have a heightened ability to process and present MHC Class I antigens. IRGM deficient cells restrict the replication of several viruses including ZIKV and SARS-CoV2. Irgm1 −/− mice are resistant to CHIKV infection. IRGM negatively regulates IFN responses and IRGM expression is increased upon viral infection. Its depletion triggers anti-viral restriction factors and promotes resistance to a large number of human viruses, including SARS-CoV2, CHIKV and ZIKV. Graphical Abstract IRGM negatively regulates IFN responses and IRGM expression is increased upon viral infection. Its depletion triggers anti-viral restriction factors and promotes resistance to a large number of human viruses, including SARS-CoV2, CHIKV and ZIKV.