Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2;Irgm1−/−) and the other with dampened IFN-I response (hACE2;Ifnar1−/−) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2;Irgm1−/−mice were resistant to lethal SARS-CoV-2 infection with substantially reduced cytokine storm and immunopathology. In striking contrast, a severe SARS-CoV-2 infection along with immune cells infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2;Ifnar1−/−mice. Additionally, hACE2;Ifnar1−/−mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2;Irgm1−/−Ifnar1−/−double knockout mice or hACE2;Irgm1−/−mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2;Irgm1−/−mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, andIrgm1(IRGM) could be an excellent therapeutic target.GRAPHICAL ABSTRACT
