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

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)

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; Nhu Thao, Tran Thi; Trüeb, Bettina Salome; Jores, Jörg and 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:

23 Sep 2022 09:09

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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