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

Cell Rep. 2023 Nov 28;42(11):113275. doi: 10.1016/j.celrep.2023.113275. Epub 2023 Oct 23.

Abstract

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.

Keywords: CP: Immunology; CP: Microbiology; Delta; IRGM; Ifnar1; Irgm1; Omicron; SARS-CoV-2; hACE2- K18 mice; interferon response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies
  • COVID-19*
  • Disease Models, Animal
  • Interferon Type I*
  • Lung
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • SARS-CoV-2

Substances

  • Interferon Type I
  • Antibodies