Impaired immune response drives age-dependent severity of COVID-19-Reference-Cited by-同舟云学术

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

Published:2022-09-21 Issue:12 Volume:219 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Beer Julius¹^ORCID,Crotta Stefania²^ORCID,Breithaupt Angele³^ORCID,Ohnemus Annette¹^ORCID,Becker Jan¹^ORCID,Sachs Benedikt¹^ORCID,Kern Lisa¹^ORCID,Llorian Miriam⁴^ORCID,Ebert Nadine⁵⁶^ORCID,Labroussaa Fabien⁶⁷^ORCID,Nhu Thao Tran Thi⁵⁶⁸^ORCID,Trueeb Bettina Salome⁶⁷^ORCID,Jores Joerg⁶⁷^ORCID,Thiel Volker⁵⁶⁹^ORCID,Beer Martin¹⁰^ORCID,Fuchs Jonas¹^ORCID,Kochs Georg¹^ORCID,Wack Andreas²^ORCID,Schwemmle Martin¹¹¹^ORCID,Schnepf Daniel¹^ORCID

Affiliation:

1. Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany 1

2. Immunoregulation Laboratory, The Francis Crick Institute, London, UK 2

3. Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany 3

4. Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK 4

5. Institute of Virology and Immunology, Bern, Switzerland 5

6. Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland 6

7. Institute of Veterinary Bacteriology, Vetsuisse Faculty, University of Bern, Bern, Switzerland 7

8. Graduate School for Biomedical Science, University of Bern, Bern, Switzerland 8

9. Multidisciplinary Center for Infectious Diseases, University of Bern, Switzerland 9

10. Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany 10

11. Faculty of Medicine, University of Freiburg, Freiburg, Germany 11

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.

Funder

Bundesministerium für Bildung und Forschung

Deutsches Zentrum für Luft- und Raumfahrt

Federal State of Baden-Wuerttemberg

Deutsche Forschungsgemeinschaft

Swiss National Science Foundation

National Centre of Competence

Francis Crick Institute

Cancer Research UK

Medical Research Council

Wellcome Trust

Publisher