Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

Type I 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 infection remains perplexing. Here, we develop 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. We report that hACE2; Irgm1−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1−/− mice. The hACE2; Irgm1−/−Ifnar1−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2. [Display omitted] •Irgm1KO mice are resistant to infection from multiple variants of SARS-CoV-2•SARS-CoV-2-infected Irgm1KO mice show attenuated inflammatory response and immunopathology•Heightened SARS-CoV-2 infection, neuroinvasion, and neuropathology are seen in Ifnar1KO mice•IFN-I response protects Irgm1KO mice from lethal SARS-CoV-2 infection The role of interferon (IFN) response in SARS-CoV-2 infection is unclear. Chauhan et al. use mouse models with heightened or blunted IFN response to show that the host IFN system is critical to resist SARS-CoV-2 infection and suggest that IRGM is a promising therapeutic target against SARS-CoV-2 and its variants.