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

All coronaviruses known to have recently emerged as human pathogens probably originated in bats 1 . 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 se...

Full description

Saved in:

Bibliographic Details
Published in:	Nature (London) Vol. 591; no. 7850; pp. 451 - 457
Main Authors:	Wahl, Angela, Gralinski, Lisa E., Johnson, Claire E., Yao, Wenbo, Kovarova, Martina, Dinnon, Kenneth H., Liu, Hongwei, Madden, Victoria J., Krzystek, Halina M., De, Chandrav, White, Kristen K., Gully, Kendra, Schäfer, Alexandra, Zaman, Tanzila, Leist, Sarah R., Grant, Paul O., Bluemling, Gregory R., Kolykhalov, Alexander A., Natchus, Michael G., Askin, Frederic B., Painter, George, Browne, Edward P., Jones, Corbin D., Pickles, Raymond J., Baric, Ralph S., Garcia, J. Victor
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-03-2021 Nature Publishing Group
Subjects:	13/31 13/51 14/28 14/32 14/63 38/90 38/91 631/326/596/2555 631/326/596/4130 64/60 82/51 Administration, Oral Alveolar Epithelial Cells - immunology Alveolar Epithelial Cells - pathology Alveolar Epithelial Cells - virology Alveoli Animals Antigens Antiviral agents Chemokines Chemoprevention Chiroptera - virology Clinical trials Clinical Trials, Phase II as Topic Clinical Trials, Phase III as Topic Coronaviridae Coronaviruses COVID-19 COVID-19 - drug therapy COVID-19 - immunology COVID-19 - prevention & control Cytidine - administration & dosage Cytidine - analogs & derivatives Cytidine - therapeutic use Cytokeratin Cytokines Cytokines - immunology Disease transmission Epithelial cells Epithelial Cells - virology Epithelium Female Heterografts Humanities and Social Sciences Humans Hydroxylamines - administration & dosage Hydroxylamines - therapeutic use Immunity, Innate Immunodeficiency Infections Inflammation Interferon Interferon Type I - immunology Lung - immunology Lung - pathology Lung - virology Lung Transplantation Lungs Male Mice Middle East respiratory syndrome multidisciplinary Pathogenesis Pathogens Pneumocytes Post-Exposure Prophylaxis Pre-Exposure Prophylaxis Prophylaxis Replication Respiratory diseases SARS-CoV-2 - immunology SARS-CoV-2 - pathogenicity Science Science (multidisciplinary) Severe acute respiratory syndrome coronavirus 2 Surgical implants Testing Viral diseases Virus Replication Viruses United States
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	All coronaviruses known to have recently emerged as human pathogens probably originated in bats 1 . 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. Human and bat coronaviruses replicate efficiently in immunodeficient mice implanted with human lung tissue, and treatment or prophylaxis using EIDD-2801 in this model suggests that this oral antiviral agent may be effective in preventing COVID-19.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Author contributions: AW, CEJ, WY, MK, and CD constructed LoM. AW contributed to experimental design, data interpretation, data presentation, and manuscript writing, coordinated the study, and the preparation of the manuscript. LEG performed the virus inoculations, animal necropsies, virus tittering, processing of lung tissues for RNA extraction, and contributed to the experimental design, planning, data analysis, data interpretation, and manuscript writing. CEJ performed immunofluorescence and H&E analyses, WY performed immunohistochemistry and H&E analyses, and MK performed the in-situ hybridization analysis of LoM human lung tissues. KHD, AS, SRL, and KG assisted with the in vivo experiments with coronavirus-infected LoMs. VJM in conjunction with KKW performed the electron microscopy analysis. GRB, AAK, MGN, and GP assisted with the EIDD-2801 experiments. FBA assisted with the pathohistological analysis. HL, HMK, TZ, POG, performed the RNA-sequencing analysis. EPB and CDJ contributed to design of RNA-sequencing experiments. RJP assisted with the immunofluorescence analysis and contributed to experimental design, data interpretation, data presentation, and manuscript writing. RSB conceived and designed experiments and contributed to data interpretation and manuscript writing. JVG conceived, designed and coordinated the study, conceived and designed experiments, and contributed to data interpretation, data presentation, and manuscript preparation.
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-021-03312-w