ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
- Medical University of Vienna, Austria
- Austrian Academy of Sciences, Austria
- Apeiron Biologics AG, Austria
- University of Natural Resources and Life Sciences, Austria
- Institute for Bioengineering of Catalonia, Spain
- Karolinska Institute, Sweden
- 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
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Exploring COVID-19 disease, immunity and therapeutic options in mice using maVie16, a host-adapted SARS-CoV-2European Nucleotide Archive (ENA), PRJEB46926.
Article and author information
Author details
Anna Ohradanova-Repic
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.
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.
Reviewing Editor
- Frank Kirchhoff, Ulm University Medical Center, Germany
Publication history
- Preprint posted: August 9, 2021 (view preprint)
- Received: October 11, 2021
- Accepted: December 22, 2021
- Accepted Manuscript published: January 13, 2022 (version 1)
- 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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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
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