Abstract
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.
【초록키워드】 COVID-19, severe COVID-19, Immunity, Antiviral, Immunotherapy, SARS-COV-2 infection, susceptibility, disease severity, interferon, mice, IFN, virus replication, Adaptive immune response, correlation, disease, function, IFN-γ, severe disease, type I, individual, increasing age, IFN-λ, Therapeutic treatment, benefit, caused, characterized, reversed, Aggravated, combinatorial treatment, 【제목키워드】 immune response, severity of COVID-19, Impaired,