Interferon Type I (IFN-I) response plays a crucial role in host defense against SARS-CoV-2 infection. Through mouse models, it has been found that a high level of IFN-I response can protect against lethal SARS-CoV-2 infection, while a dampened IFN-I response may lead to severe infection and immune inflammation.
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 damp-ened 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 pro-tects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2.
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