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

doi:10.1038/s41586-021-03312-w

. 2021 Mar;591(7850):451-457.

doi: 10.1038/s41586-021-03312-w. Epub 2021 Feb 9.

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

Angela Wahl^#^{1

2

3}, Lisa E Gralinski^#⁴, Claire E Johnson^{1

2

3}, Wenbo Yao^{1

2

3}, Martina Kovarova^{1

2

3}, Kenneth H Dinnon 3rd^{4

5}, Hongwei Liu^{6

7}, Victoria J Madden⁸, Halina M Krzystek^{6

7}, Chandrav De^{1

2

3}, Kristen K White⁸, Kendra Gully⁴, Alexandra Schäfer⁴, Tanzila Zaman^{6

7}, Sarah R Leist⁴, Paul O Grant^{6

7}, Gregory R Bluemling^{9

10}, Alexander A Kolykhalov^{9

10}, Michael G Natchus¹⁰, Frederic B Askin¹¹, George Painter^{9

10

12}, Edward P Browne^{2

3

5

13}, Corbin D Jones^{6

7}, Raymond J Pickles^{5

14}, Ralph S Baric^{4

5

15}, J Victor Garcia^{16

17

18}

Affiliations

¹ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA.
¹⁰ Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA, USA.
¹¹ Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA.
¹³ UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Marsico Lung Institute, University of North Carolina at Chapel, Chapel Hill, NC, USA.
¹⁵ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
¹⁷ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
¹⁸ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.

^# Contributed equally.

PMID: 33561864
PMCID: PMC7979515
DOI: 10.1038/s41586-021-03312-w

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

Angela Wahl et al. Nature. 2021 Mar.

. 2021 Mar;591(7850):451-457.

doi: 10.1038/s41586-021-03312-w. Epub 2021 Feb 9.

Authors

Affiliations

¹ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA.
¹⁰ Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA, USA.
¹¹ Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA.
¹³ UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Marsico Lung Institute, University of North Carolina at Chapel, Chapel Hill, NC, USA.
¹⁵ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
¹⁷ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
¹⁸ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.

^# Contributed equally.

PMID: 33561864
PMCID: PMC7979515
DOI: 10.1038/s41586-021-03312-w

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.

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Conflict of interest statement

Competing interests: GP, MGN, GRB and AAK are employees of Emory and have a financial interest in molnupiravir (EIDD-2801).

Additional Information

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this paper.

Figures

**Extended Data Fig. 1.. Human epithelial cells in the human lung tissue of LoMs express ACE2.**
a, H&E staining of the human lung tissue of a naïve LoM (scale bars 500 um [left image] and 100 um [right images], n=6). Boxes indicate regions shown in higher magnification images (right images) of cartilaginous airways (top) and non-cartilaginous airways and alveoli (bottom). Immunofluorescence staining for b, human cytokeratin 19 (epithelial cells, green; nuclei, blue; scale bar 50 um), CD34 (endothelial cells, green; nuclei, blue; scale bar 50 um), and vimentin (mesenchymal cells, green; nuclei, blue; scale bar 50 um). n=8 tissues analyzed. c, human ACE2 in the human lung tissue of a naïve LoM (positive cells, red; nuclei, blue; scale bar 50 um, n=9). d, Co-staining for human ACE2 (positive cells, red) and cytokeratin 19 (positive cells, green) in naïve LoM human lung tissue (nuclei, blue; scale bar 50 um, n=9). e, Immunohistochemical staining for TMPRSS2 in naïve LoM human lung tissue (positive cells, brown; scale bar, 100 um; n=6). n=number of biologically independent lung tissues analyzed.

**Extended Data Fig. 2.. Viral nucleoprotein in the human lung tissues of LoM infected with recently emerged human coronaviruses and bat coronaviruses.**
Immunohistochemical staining for virus nucleoprotein in human lung tissue collected from a, LoM two days post exposure to recently emerged human coronaviruses SARS-CoV (n=4), MERS-CoV (n=5), or SARS-CoV-2 (n=6), b, LoM two days post exposure to bat coronaviruses WIV1-CoV or SHC014-CoV (n=10), or c, naïve LoM (n=6). Positive cells, brown. Scale bars, 100 um. n=number of biologically independent lung tissues analyzed.

**Extended Data Fig. 3.. SARS-CoV-2 infection of human epithelial cell types in the human lung tissue of LoM.**
Single color and merged images of those shown in Fig. 1f and g depicting co-staining of LoM human lung tissue two days following SARS-CoV-2 exposure for virus nucleoprotein (red) and a, and cytokeratin 19 (epithelial cells, green, n=6), CD34 (endothelial cells, green, n= 4), or vimentin (mesenchymal cells, green, n=4) or b, acetylated alpha-tubulin IV (ciliated cells, green, n=6), CC10 (club cells, green, n=6), HT1–56 (alveolar type 1 cells, green, n=6), or Pro-SP-C (alveolar type 2 cells, green, n=3). Nuclei, blue; scale bars 50 um. n=number of biologically independent lung tissues analyzed.

**Extended Data Fig. 4.. Experimental design for the evaluation of EIDD-2801 as treatment or pre-exposure prophylaxis for SARS-CoV-2 infection.**
a, Treatment experimental design. LoM were orally administered EIDD-2801 or vehicle at 24 h or 48 h post SARS-CoV-2 exposure and every 12 h thereafter. Virus titers were measured 2 days post-treatment initiation. b, Pre-exposure prophylaxis experimental design. LoM were orally administered EIDD-2801 or vehicle control 12 h prior to SARS-CoV-2 exposure and every 12 h thereafter. Virus titers in human lung tissues were measured 2 days post-exposure.

Fig. 1.. Robust replication of recently emerged human and bat coronaviruses in LoM demonstrate the potential of bat coronaviruses for direct transmission to humans and the predilection of SARS-CoV-2 for infection of human epithelial cells.
a, LoM construction and image of a human lung implant. b, Viral titers in the human lung tissue of LoM injected with SARS-CoV (n=14, red), MERS-CoV (n=16, orange), SARS-CoV-2 (n=7, blue), WIV1-CoV (n=6, green), or SHC014 (n=6, purple) as determined by plaque assay (PFU, plaque forming units). c, SARS-CoV-2 titers in the human lung tissue of LoM at days 2 (n=6), 6 (n=6), and 14 (n=6) post-exposure were compared with a two-sided Kruskal-Wallis with Dunn’s multiple comparisons test. d, SARS-CoV-2 RNA in LoM human lung tissue 2 days post-exposure (SARS-CoV-2 RNA+, red; nuclei, blue; scale bars, 750 um [left image] and 250 um [right images], n=3). e, Virus nucleoprotein in LoM human lung tissue two-days post-exposure (positive cells, red; nuclei, blue; scale bars 200 um [left image] and 50 um [right images], n=6). f, Co-staining of LoM human lung tissue two days following SARS-CoV-2 exposure for virus nucleoprotein (red) and cytokeratin 19 (epithelial cells, green, n=6), CD34 (endothelial cells, green, n= 4), or vimentin (mesenchymal cells, green, n=4). Nuclei, blue; scale bars 50 um. g, Co-staining of LoM human lung tissue two days following SARS-CoV-2 exposure for virus nucleoprotein (red) and acetylated alpha-tubulin IV (ciliated cells, green, n=6), CC10 (club cells, green, n=6), HT1–56 (alveolar type 1 cells, green, n=6), or Pro-SP-C (alveolar type 2 cells, green, n=3). Nuclei, blue; scale bars 50 um. In b and c, horizontal and vertical lines represent the median and interquartile range respectively. n= number of biologically independent lung tissues analyzed.

**Fig. 2.. Acute SARS-CoV-2 infection is highly cytopathic and causes extensive damage to human lung structures.**
a, H&E staining of a SARS-CoV-2 infected LoM human lung tissue 2 days post-exposure (scale bar, 100 um, n=6). Arrows indicate protein globules. **b-d**, Immunohistochemical staining for virus nucleoprotein in LoM human lung tissue 2 days following SARS-CoV-2 exposure (positive cells, brown; b scale bars, 100 um; c and d scale bars, 50 um, n=6). **e-g**, Martius Scarlet Blue staining of human lung tissue from e, naïve LoM (n=6) and f and g, SARS-CoV-2 infected LoM 2 days post-exposure (scale bars, 50 um; fibrin, red; collagen, blue, n=6). Arrows indicate the presence of fibrin (red) in f, alveoli or in g, thrombi of occluded vessels. **h-l**, Electron microscopy analysis of SARS-CoV-2 infected human lung tissue two days post-exposure (n=3). h, Uninfected AT2 cells in an alveolus-like structure. Scale bars, 2 um. i, SARS-CoV-2 infected AT2 cell. Higher magnification images of boxed areas show virus particles with dense nucleocapsids in RER. Scale bars, 2 um (left image), 1 um (middle image), and 200 nm (right image). j, Degenerative SARS-CoV-2 infected cell in the alveolar space. Arrows indicate virus filled vesicles. Scale bars, 1 um (left image), 200 nm (middle image), and 100 nm (right image). k and l, Blood vessels containing virions, fibrillar protein and cell debris. In k, scale bars, 5 um (left image) and 500 nm (right image). In l, scale bars, 2 um (right image) and 200 nm (left image). AS, alveolar space; AT1, alveolar type 1 cells; AT2, alveolar type 2 cells; BV, blood vessel; C, collagen; G, glycogen; LB, lamellar body; M, mitochondria; MO, monocyte; MV, microvilli; RER, rough endoplasmic reticulum. In c, **i-l**, black boxes indicate areas of higher magnification images. n= number of biologically independent lung tissues analyzed.

**Fig. 3.. SARS-CoV-2 infection induces a strong and sustained host innate immune response in human lung tissue.**
**a-d**, RNA-sequencing analysis of human lung tissue collected from SARS-CoV-2 infected LoM. a, Log₁₀ gene transcripts per million (TPM) in the human lungs of naïve LoM (n=2, x-axis) and SARS-CoV-2 infected (n=2, y-axis) LoM day 2 post-exposure. Genes of interest from Supplementary Tables 1 and 2 that appear increased (red) or decreased (blue) at least two-fold in SARS-CoV-2 infected LoM are shown. Genes having zero (0) mean TPM in either naïve or infected LoM are set at a minimum of log10 (0.0001) TPM in order to visualize. b, Gene set enrichment analysis (GSEA) identified gene sets enriched in SARS-CoV-2 infected LoM human lungs. The pathway enrichment score is shown on the x-axis. The statistical significance of enrichment scores was determined using a two-sided empirical phenotype-based permutation test and adjusted for multiple testing using a False Discovery Rate (red, p<0.05). Heatmaps illustrating the expression of human c, interferon genes and d, cytokine/chemokine genes in human lung tissue collected analyzed from SARS-CoV-2 infected LoM days 2 (n=2), 6 (n=3), and 14 (n=3) post-exposure and naïve LoMs (n=4). Color scale indicates the mean log₁₀ TPM. n= number of biologically independent lung tissues analyzed.

**Fig. 4.. Treatment and pre-exposure prophylaxis with EIDD-2801, a broad-spectrum anti-coronavirus drug, potently inhibit SARS-CoV-2 infection *in vivo*.**
a, SARS-CoV-2 titers in the human lung tissue of LoM administered EIDD-2801 (n=8) or vehicle (n=8) 24 h post virus exposure. b, SARS-CoV-2 titers in the human lung tissue of LoM administered EIDD-2801 (n=8) or vehicle (n=8) 48 h post virus exposure. c and d, SARS-CoV-2 titers in the human lung tissue of LoM administered EIDD-2801 (n=8 per experiment, yellow) or control vehicle (Ctrl, n=8 per experiment, blue) at 2 days post-exposure in two independent experiments shown c, separately and d, combined. e, Fold difference in SARS-CoV-2 titers in the human lung tissue of LoM relative to vehicle controls. f, H&E staining and g, immunohistochemical staining for virus nucleoprotein (positive cells, brown) of human lung tissue of LoM administered EIDD-2801 (n=8) or control vehicle (Ctrl, n=8) at 2 days post-exposure (scale bars, 100 um). **a-d,** Titers were compared with a two-tailed Mann-Whitney U test. Horizontal and vertical lines represent the median and interquartile range respectively. n= number of biologically independent lung tissues analyzed.

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Update of

Acute SARS-CoV-2 Infection is Highly Cytopathic, Elicits a Robust Innate Immune Response and is Efficiently Prevented by EIDD-2801.
Wahl A, Gralinski L, Johnson C, Yao W, Kovarova M, Dinnon K, Liu H, Madden V, Krzystek H, De C, White K, Schäfer A, Zaman T, Leist S, Grant P, Gully K, Askin F, Browne E, Jones C, Pickles R, Baric R, Garcia JV. Wahl A, et al. Res Sq [Preprint]. 2020 Sep 24:rs.3.rs-80404. doi: 10.21203/rs.3.rs-80404/v1. Res Sq. 2020. Update in: Nature. 2021 Mar;591(7850):451-457. doi: 10.1038/s41586-021-03312-w. PMID: 32995766 Free PMC article. Updated. Preprint.

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References

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[1] Cui J, Li F & Shi ZL Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17, 181–192, doi:10.1038/s41579-018-0118-9 (2019). - DOI - PMC - PubMed

[2] Cui J, Li F & Shi ZL Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17, 181–192, doi:10.1038/s41579-018-0118-9 (2019). - DOI - PMC - PubMed

[3] Dong E, Du H & Gardner L An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 20, 533–534, doi:10.1016/S1473-3099(20)30120-1 (2020). - DOI - PMC - PubMed

[4] Dong E, Du H & Gardner L An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 20, 533–534, doi:10.1016/S1473-3099(20)30120-1 (2020). - DOI - PMC - PubMed

[5] Boni MF et al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol, doi:10.1038/s41564-020-0771-4 (2020). - DOI - PubMed

[6] Boni MF et al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol, doi:10.1038/s41564-020-0771-4 (2020). - DOI - PubMed

[7] Bao L et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, doi:10.1038/s41586-020-2312-y (2020). - DOI - PubMed

[8] Bao L et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, doi:10.1038/s41586-020-2312-y (2020). - DOI - PubMed

[9] Blanco-Melo D et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 181, 1036–1045 e1039, doi:10.1016/j.cell.2020.04.026 (2020). - DOI - PMC - PubMed

[10] Blanco-Melo D et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 181, 1036–1045 e1039, doi:10.1016/j.cell.2020.04.026 (2020). - DOI - PMC - PubMed

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