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

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 Gully, Alexandra Schäfer, Tanzila Zaman, Sarah R. Leist, Paul O. Grant, Gregory R. Bluemling, Alexander A. Kolykhalov, Michael G. Natchus, Frederic B. Askin, George Painter, Edward P. Browne, Corbin D. Jones, Raymond J. Pickles, Ralph S. Baric and J. Victor Garcia ()
Additional contact information
Angela Wahl: 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
Wenbo Yao: University of North Carolina at Chapel Hill
Martina Kovarova: University of North Carolina at Chapel Hill
Kenneth H. Dinnon: University of North Carolina at Chapel Hill
Hongwei Liu: 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
Chandrav De: 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
Sarah R. Leist: University of North Carolina at Chapel Hill
Paul O. Grant: University of North Carolina at Chapel Hill
Gregory R. Bluemling: Emory University
Alexander A. Kolykhalov: Emory University
Michael G. Natchus: Drug Innovation Ventures at Emory (DRIVE)
Frederic B. Askin: University of North Carolina at Chapel Hill
George Painter: Emory University
Edward P. Browne: University of North Carolina at Chapel Hill
Corbin D. Jones: University of North Carolina at Chapel Hill
Raymond J. Pickles: University of North Carolina at Chapel Hill
Ralph S. Baric: University of North Carolina at Chapel Hill
J. Victor Garcia: University of North Carolina at Chapel Hill

Nature, 2021, vol. 591, issue 7850, 451-457

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03312-w

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