ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

  1. Riem Gawish
  2. Philipp Starkl
  3. Lisabeth Pimenov
  4. Anastasiya Hladik
  5. Karin Lakovits
  6. Felicitas Oberndorfer
  7. Shane JF Cronin
  8. Anna Ohradanova-Repic
  9. Gerald Wirnsberger
  10. Benedikt Agerer
  11. Lukas Endler
  12. Tümay Capraz
  13. Jan W Perthold
  14. Domagoj Cikes
  15. Rubina Koglgruber
  16. Astrid Hagelkruys
  17. Nuria Montserrat
  18. Ali Mirazimi
  19. Louis Boon
  20. Hannes Stockinger
  21. Andreas Bergthaler
  22. Chris Oostenbrink
  23. Josef M Penninger
  24. Sylvia Knapp  Is a corresponding author
  1. Medical University of Vienna, Austria
  2. Austrian Academy of Sciences, Austria
  3. Apeiron Biologics AG, Austria
  4. University of Natural Resources and Life Sciences, Austria
  5. Institute for Bioengineering of Catalonia, Spain
  6. Karolinska Institute, Sweden
  7. Polpharma Biologics, Netherlands

Abstract

In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

Data availability

maVie16 SARS-CoV-2 genome sequence will be published on: https://www.ebi.ac.uk/enaProjectaccession: PRJEB46926

The following data sets were generated

Article and author information

Author details

  1. Riem Gawish

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4267-2131
  2. Philipp Starkl

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
  3. Lisabeth Pimenov

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
  4. Anastasiya Hladik

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
  5. Karin Lakovits

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
  6. Felicitas Oberndorfer

    Department of Pathology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
  7. Shane JF Cronin

    Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  8. Anna Ohradanova-Repic

    Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8005-8522
  9. Gerald Wirnsberger

    Apeiron Biologics AG, Vienna, Austria
    Competing interests
    Gerald Wirnsberger, is an employee of Apeiron Biologics. Apeiron holds a patent on the use of ACE2 for the treatment of lung, heart, or kidney injury and is currently testing soluble ACE2 for treatment in COVID-19 patients..
  10. Benedikt Agerer

    CeMM, Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  11. Lukas Endler

    CeMM, Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  12. Tümay Capraz

    Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  13. Jan W Perthold

    Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  14. Domagoj Cikes

    Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  15. Rubina Koglgruber

    Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  16. Astrid Hagelkruys

    Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  17. Nuria Montserrat

    Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia, Barcelona, Spain
    Competing interests
    No competing interests declared.
  18. Ali Mirazimi

    Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  19. Louis Boon

    Polpharma Biologics, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  20. Hannes Stockinger

    Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6404-4430
  21. Andreas Bergthaler

    CeMM, Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
  22. Chris Oostenbrink

    Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4232-2556
  23. Josef M Penninger

    Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    Josef M Penninger, declares a conflict of interest as a founder and shareholder of Apeiron Biologics. Apeiron holds a patent on the use of ACE2 for the treatment of lung, heart, or kidney injury and is currently testing soluble ACE2 for treatment in COVID-19 patients.(patent #WO2021191436A1)..
  24. Sylvia Knapp

    Department of Medicine I, Medical University of Vienna, Vienna, Austria
    For correspondence
    Sylvia.knapp@meduniwien.ac.at
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9016-5244

Funding

Austrian Science Fund (F54-10 and F61-04)

  • Sylvia Knapp

Innovative Medicines Initiative (101005026)

  • Josef M Penninger

Austrian Science Fund (ZK57-B28)

  • Riem Gawish

Austrian Science Fund (P31113-B30)

  • Philipp Starkl

Austrian Science Fund (P 34253-B)

  • Anna Ohradanova-Repic

Austrian Science Fund (P 34253-B)

  • Hannes Stockinger

Austrian Science Fund (DK W1212)

  • Benedikt Agerer

Austrian Science Fund (Z 271-B19)

  • Josef M Penninger

Canada Research Chairs (F18-01336)

  • Josef M Penninger

Canadian Institutes of Health Research (F20-02343 and F20-02015)

  • Josef M Penninger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank Kirchhoff, Ulm University Medical Center, Germany

Ethics

Animal experimentation: All experiments involving SARS-CoV-2 or its derivatives were performed in Biosafety Level 3 (BSL-3) facilities at the Medical University of Vienna and performed according to the ethical guidelines and after approval by the institutional review board of the Austrian Ministry of Sciences (BMBWF-2020-0.253.770) and in accordance with the directives of the EU.

Version history

  1. Preprint posted: August 9, 2021 (view preprint)
  2. Received: October 11, 2021
  3. Accepted: December 22, 2021
  4. Accepted Manuscript published: January 13, 2022 (version 1)
  5. Version of Record published: January 20, 2022 (version 2)

Copyright

© 2022, Gawish et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Riem Gawish
  2. Philipp Starkl
  3. Lisabeth Pimenov
  4. Anastasiya Hladik
  5. Karin Lakovits
  6. Felicitas Oberndorfer
  7. Shane JF Cronin
  8. Anna Ohradanova-Repic
  9. Gerald Wirnsberger
  10. Benedikt Agerer
  11. Lukas Endler
  12. Tümay Capraz
  13. Jan W Perthold
  14. Domagoj Cikes
  15. Rubina Koglgruber
  16. Astrid Hagelkruys
  17. Nuria Montserrat
  18. Ali Mirazimi
  19. Louis Boon
  20. Hannes Stockinger
  21. Andreas Bergthaler
  22. Chris Oostenbrink
  23. Josef M Penninger
  24. Sylvia Knapp
(2022)
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
eLife 11:e74623.
https://doi.org/10.7554/eLife.74623

Share this article

https://doi.org/10.7554/eLife.74623

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