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Nature
03, 2021;591 (7850): 451-457.

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, J Victor Garcia
Author Information
  1. Angela Wahl: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  2. Lisa E Gralinski: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  3. Claire E Johnson: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  4. Wenbo Yao: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  5. Martina Kovarova: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  6. Kenneth H Dinnon: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  7. Hongwei Liu: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  8. Victoria J Madden: Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  9. Halina M Krzystek: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  10. Chandrav De: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  11. Kristen K White: Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  12. Kendra Gully: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  13. Alexandra Schäfer: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  14. Tanzila Zaman: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  15. Sarah R Leist: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  16. Paul O Grant: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  17. Gregory R Bluemling: Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA. ORCID
  18. Alexander A Kolykhalov: Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA.
  19. Michael G Natchus: Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA, USA.
  20. Frederic B Askin: Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  21. George Painter: Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA.
  22. Edward P Browne: Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  23. Corbin D Jones: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  24. Raymond J Pickles: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  25. Ralph S Baric: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  26. J Victor Garcia: International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu. ORCID
PMID: 33561864 DOI: 10.1038/s41586-021-03312-w

Abstract

All coronaviruses known to have recently emerged as human pathogens probably originated in bats. 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.

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Grants

  1. R21 AI113736/NIAID NIH HHS
  2. R01 MH108179/NIMH NIH HHS
  3. R01 AI123010/NIAID NIH HHS
  4. R01 AI108197/NIAID NIH HHS
  5. P30 CA016086/NCI NIH HHS
  6. R01 AI140799/NIAID NIH HHS
  7. R21 AI138247/NIAID NIH HHS
  8. R01 AI111899/NIAID NIH HHS
  9. U19 AI100625/NIAID NIH HHS
  10. P30 AI050410/NIAID NIH HHS

MeSH Term

Administration, Oral
Alveolar Epithelial Cells
Animals
COVID-19
Chemoprevention
Chiroptera
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
Cytidine
Cytokines
Epithelial Cells
Female
Heterografts
Humans
Hydroxylamines
Immunity, Innate
Interferon Type I
Lung
Lung Transplantation
Male
Mice
Post-Exposure Prophylaxis
Pre-Exposure Prophylaxis
SARS-CoV-2
Virus Replication
COVID-19 Drug Treatment

Chemicals

Cytokines
Hydroxylamines
Interferon Type I
Cytidine
molnupiravir
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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