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

Advanced age is the most critical risk factor for severe COVID-19. Using a newly established mouse model, Beer et al. demonstrate that the age-dependent exacerbation of disease is driven by a diminished innate and adaptive immune response due to impaired type I and type II interferon responses. 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-gamma response and excessive virus replication. Accordingly, adult IFN-gamma receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-gamma reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-lambda in adults and a combinatorial treatment with IFN-gamma and IFN-lambda 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-gamma and IFN-lambda.