Impaired immune response drives age-dependent severity of COVID-19More about Open Access at the Crick
Authors listJulius Beer Stefania Crotta Angele Breithaupt Annette Ohnemus Jan Becker Benedikt Sachs Lisa Kern Miriam Llorian Nadine Ebert Fabien Labroussaa Tran Thi Nhu Thao Bettina Salome Trueeb Joerg Jores Volker Thiel Martin Beer Jonas Fuchs Georg Kochs Andreas Wack Martin Schwemmle Daniel Schnepf
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.
Journal Journal of Experimental Medicine
Issue number 12