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A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Author

Listed:
  • Kenneth H. Dinnon

    (University of North Carolina at Chapel Hill)

  • Sarah R. Leist

    (University of North Carolina at Chapel Hill)

  • Alexandra Schäfer

    (University of North Carolina at Chapel Hill)

  • Caitlin E. Edwards

    (University of North Carolina at Chapel Hill)

  • David R. Martinez

    (University of North Carolina at Chapel Hill)

  • Stephanie A. Montgomery

    (University of North Carolina)

  • Ande West

    (University of North Carolina at Chapel Hill)

  • Boyd L. Yount

    (University of North Carolina at Chapel Hill)

  • Yixuan J. Hou

    (University of North Carolina at Chapel Hill)

  • Lily E. Adams

    (University of North Carolina at Chapel Hill)

  • Kendra L. Gully

    (University of North Carolina at Chapel Hill)

  • Ariane J. Brown

    (University of North Carolina at Chapel Hill)

  • Emily Huang

    (University of North Carolina at Chapel Hill)

  • Matthew D. Bryant

    (Eiger BioPharmaceuticals)

  • Ingrid C. Choong

    (Eiger BioPharmaceuticals)

  • Jeffrey S. Glenn

    (Stanford University
    Palo Alto Veterans Administration)

  • Lisa E. Gralinski

    (University of North Carolina at Chapel Hill)

  • Timothy P. Sheahan

    (University of North Carolina at Chapel Hill)

  • Ralph S. Baric

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina)

Abstract

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro—both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-196.

Suggested Citation

  • Kenneth H. Dinnon & Sarah R. Leist & Alexandra Schäfer & Caitlin E. Edwards & David R. Martinez & Stephanie A. Montgomery & Ande West & Boyd L. Yount & Yixuan J. Hou & Lily E. Adams & Kendra L. Gully , 2020. "A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures," Nature, Nature, vol. 586(7830), pages 560-566, October.
  • Handle: RePEc:nat:nature:v:586:y:2020:i:7830:d:10.1038_s41586-020-2708-8
    DOI: 10.1038/s41586-020-2708-8
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    Citations

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    Cited by:

    1. Yu-Wei Luo & Jiang-Peng Zhou & Hongyu Ji & Doudou Xu & Anqi Zheng & Xin Wang & Zhizheng Dai & Zhicheng Luo & Fang Cao & Xing-Yue Wang & Yunfang Bai & Di Chen & Yueming Chen & Qi Wang & Yaying Yang & X, 2024. "SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Dennis Lapuente & Jana Fuchs & Jonas Willar & Ana Vieira Antão & Valentina Eberlein & Nadja Uhlig & Leila Issmail & Anna Schmidt & Friederike Oltmanns & Antonia Sophia Peter & Sandra Mueller-Schmucker, 2021. "Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Raveen Rathnasinghe & Sonia Jangra & Chengjin Ye & Anastasija Cupic & Gagandeep Singh & Carles Martínez-Romero & Lubbertus C. F. Mulder & Thomas Kehrer & Soner Yildiz & Angela Choi & Stephen T. Yeung , 2022. "Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Davida S. Smyth & Monica Trujillo & Devon A. Gregory & Kristen Cheung & Anna Gao & Maddie Graham & Yue Guan & Caitlyn Guldenpfennig & Irene Hoxie & Sherin Kannoly & Nanami Kubota & Terri D. Lyddon & M, 2022. "Tracking cryptic SARS-CoV-2 lineages detected in NYC wastewater," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Matthew R. Chang & Luke Tomasovic & Natalia A. Kuzmina & Adam J. Ronk & Patrick O. Byrne & Rebecca Johnson & Nadia Storm & Eduardo Olmedillas & Yixuan J. Hou & Alexandra Schäfer & Sarah R. Leist & Lon, 2022. "IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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