Impaired immune response drives age-dependent severity of COVID-19

J Exp Med. 2022 Dec 5;219(12):e20220621. doi: 10.1084/jem.20220621. Epub 2022 Sep 21.


Severity of COVID-19 shows an extraordinary correlation with increasing age. We generated a mouse model for severe COVID-19 and show that the age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-λ in adults and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1-/- mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity and clarify the nonredundant antiviral functions of type I, II, and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-γ and IFN-λ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents
  • COVID-19*
  • Immunity
  • Interferons
  • Mice
  • SARS-CoV-2


  • Antiviral Agents
  • Interferons