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

Julius Beer, View ORCID ProfileStefania Crotta, View ORCID ProfileAngele Breithaupt, View ORCID ProfileAnnette Ohnemus, View ORCID ProfileJan Becker, Benedikt Sachs, Lisa Kern, Miriam Llorian, Nadine Ebert, View ORCID ProfileFabien Labroussaa, Tran Thi Nhu Thao, View ORCID ProfileBettina Salome Trueeb, View ORCID ProfileJoerg Jores, View ORCID ProfileVolker Thiel, Martin Beer, View ORCID ProfileJonas Fuchs, View ORCID ProfileGeorg Kochs, View ORCID ProfileAndreas Wack, View ORCID ProfileMartin Schwemmle, View ORCID ProfileDaniel Schnepf
doi: https://doi.org/10.1101/2022.04.21.489072
Julius Beer
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Stefania Crotta
2Immunoregulation Laboratory, The Francis Crick Institute, London, UK
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Angele Breithaupt
3Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Annette Ohnemus
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Jan Becker
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Benedikt Sachs
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Lisa Kern
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Miriam Llorian
4Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK
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Nadine Ebert
5Institute of Virology and Immunology (IVI), Bern and Mittelhäusern, Switzerland
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Fabien Labroussaa
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
7Institute of Veterinary Bacteriology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Tran Thi Nhu Thao
5Institute of Virology and Immunology (IVI), Bern and Mittelhäusern, Switzerland
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
8Graduate School for Biomedical Science, University of Bern, Bern, Switzerland
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Bettina Salome Trueeb
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
7Institute of Veterinary Bacteriology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Joerg Jores
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
7Institute of Veterinary Bacteriology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Volker Thiel
5Institute of Virology and Immunology (IVI), Bern and Mittelhäusern, Switzerland
6Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
9Multidisciplinary Center for Infectious Diseases, University of Bern, Switzerland
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Martin Beer
10Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
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Jonas Fuchs
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Georg Kochs
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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Andreas Wack
2Immunoregulation Laboratory, The Francis Crick Institute, London, UK
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Martin Schwemmle
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
11Faculty of Medicine, University of Freiburg, Freiburg, Germany
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  • For correspondence: daniel.schnepf@uniklinik-freiburg.de
Daniel Schnepf
1Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
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  • ORCID record for Daniel Schnepf
  • For correspondence: daniel.schnepf@uniklinik-freiburg.de
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Abstract

SARS-CoV-2 is a highly contagious respiratory virus and the causative agent for COVID-19. The severity of disease varies from mildly symptomatic to lethal and shows an extraordinary correlation with increasing age, which represents the major risk factor for severe COVID-191. However, the precise pathomechanisms leading to aggravated disease in the elderly are currently unknown. Delayed and insufficient antiviral immune responses early after infection as well as dysregulated and overshooting immunopathological processes late during disease were suggested as possible mechanisms. Here we show that the age-dependent increase of COVID-19 severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) responses. To overcome the limitations of mechanistic studies in humans, we generated a mouse model for severe COVID-19 and compared the kinetics of the immune responses in adult and aged mice at different time points after infection. 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.

Mimicking impaired type I IFN immunity in adult and aged mice, a second major risk factor for severe COVID-192–4, we found that therapeutic treatment with IFN-λ in adult 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 of COVID-19 and clarify the nonredundant antiviral functions of type I, II and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Based on our data, we suggest that highly vulnerable individuals combining both risk factors, advanced age and an impaired type I IFN immunity, may greatly benefit from immunotherapy combining IFN-γ and IFN-λ.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 22, 2022.
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Impaired immune response drives age-dependent severity of COVID-19
Julius 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
bioRxiv 2022.04.21.489072; doi: https://doi.org/10.1101/2022.04.21.489072
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Impaired immune response drives age-dependent severity of COVID-19
Julius 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
bioRxiv 2022.04.21.489072; doi: https://doi.org/10.1101/2022.04.21.489072

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