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SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801

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Listed:
  • Angela Wahl

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

  • Lisa E. Gralinski

    (University of North Carolina at Chapel Hill)

  • Claire E. Johnson

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

  • Wenbo Yao

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

  • Martina Kovarova

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

  • Kenneth H. Dinnon

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

  • Hongwei Liu

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

  • Victoria J. Madden

    (University of North Carolina at Chapel Hill)

  • Halina M. Krzystek

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

  • Chandrav De

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

  • Kristen K. White

    (University of North Carolina at Chapel Hill)

  • Kendra Gully

    (University of North Carolina at Chapel Hill)

  • Alexandra Schäfer

    (University of North Carolina at Chapel Hill)

  • Tanzila Zaman

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

  • Sarah R. Leist

    (University of North Carolina at Chapel Hill)

  • Paul O. Grant

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

  • Gregory R. Bluemling

    (Emory University
    Drug Innovation Ventures at Emory (DRIVE))

  • Alexander A. Kolykhalov

    (Emory University
    Drug Innovation Ventures at Emory (DRIVE))

  • Michael G. Natchus

    (Drug Innovation Ventures at Emory (DRIVE))

  • Frederic B. Askin

    (University of North Carolina at Chapel Hill)

  • George Painter

    (Emory University
    Drug Innovation Ventures at Emory (DRIVE)
    Emory University)

  • Edward P. Browne

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

  • Corbin D. Jones

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

  • Raymond J. Pickles

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

  • Ralph S. Baric

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

  • J. Victor Garcia

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

Abstract

All coronaviruses known to have recently emerged as human pathogens probably originated in bats1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801—an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials—markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.

Suggested Citation

  • Angela Wahl & Lisa E. Gralinski & Claire E. Johnson & Wenbo Yao & Martina Kovarova & Kenneth H. Dinnon & Hongwei Liu & Victoria J. Madden & Halina M. Krzystek & Chandrav De & Kristen K. White & Kendra, 2021. "SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801," Nature, Nature, vol. 591(7850), pages 451-457, March.
    • Handle: RePEc:nat:nature:v:591:y:2021:i:7850:d:10.1038_s41586-021-03312-w
    DOI: 10.1038/s41586-021-03312-w
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    Cited by:

    1. Carolin M. Lieber & Robert M. Cox & Julien Sourimant & Josef D. Wolf & Kate Juergens & Quynh Phung & Manohar T. Saindane & Meghan K. Smith & Zachary M. Sticher & Alexander A. Kalykhalov & Michael G. N, 2022. "SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Haiqing Bai & Longlong Si & Amanda Jiang & Chaitra Belgur & Yunhao Zhai & Roberto Plebani & Crystal Yuri Oh & Melissa Rodas & Aditya Patil & Atiq Nurani & Sarah E. Gilpin & Rani K. Powers & Girija Goy, 2022. "Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Nobuyo Higashi-Kuwata & Kohei Tsuji & Hironori Hayashi & Haydar Bulut & Maki Kiso & Masaki Imai & Hiromi Ogata-Aoki & Takahiro Ishii & Takuya Kobayakawa & Kenta Nakano & Nobutoki Takamune & Naoki Kish, 2023. "Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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