Beer, Julius; Crotta, Stefania; Breithaupt, Angele; Ohnemus, Annette; Becker, Jan; Sachs, Benedikt; Kern, Lisa; Llorian, Miriam; Ebert, Nadine; Labroussaa, Fabien; Nhu Thao, Tran Thi; Trueeb, Bettina Salome; Jores, Joerg; Thiel, Volker; Beer, Martin; Fuchs, Jonas; Kochs, Georg; Wack, Andreas; Schwemmle, Martin and Schnepf, Daniel (2022). Impaired immune response drives age-dependent severity of COVID-19. The Journal of experimental medicine, 219(12) Rockefeller Univ. Press 10.1084/jem.20220621
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Veterinary Bacteriology |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Ebert, Nadine, Labroussaa, Fabien, Tran, Thi Nhu Thao, Trüeb, Bettina Salome, Jores, Jörg, Thiel, Volker Earl |
Subjects: |
600 Technology > 630 Agriculture |
ISSN: |
1540-9538 |
Publisher: |
Rockefeller Univ. Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Sep 2022 09:00 |
Last Modified: |
02 Mar 2023 23:36 |
Publisher DOI: |
10.1084/jem.20220621 |
PubMed ID: |
36129445 |
BORIS DOI: |
10.48350/173155 |
URI: |
https://boris.unibe.ch/id/eprint/173155 |
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