SARS-CoV-2 D614G Variant Exhibits Efficient Replication  ex vivo  and Transmission  in vivo

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Abstract

The spike D614G substitution is prevalent in global SARS-CoV-2 strains, but its effects on viral pathogenesis and transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells, but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.

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Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus

B Korber, W.M. Fischer, S. Gnanakaran … (2020)

Summary A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to the introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to higher titer as pseudotyped virions. In infected individuals G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, although not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus, and support continuing surveillance of Spike mutations to aid in the development of immunological interventions.

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SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Waradon Sungnak, Ni Huang, Christophe Bécavin … (2020)

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.

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The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity

Qianqian Li, Jiajing Wu, Jianhui Nie … (2020)

Summary The spike protein of SARS-CoV-2 has been undergoing mutations and is highly glycosylated. It is critically important to investigate the biological significance of these mutations. Here we investigated 80 variants and 26 glycosylation site modifications for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants containing both D614G and another amino acid change, were significantly more infectious. Most variants with amino acid change at receptor binding domain were less infectious but variants including A475V, L452R, V483A and F490L became resistant to some neutralizing antibodies. Moreover, the majority of glycosylation deletions were less infectious whilst deletion of both N331 and N343 glycosylation drastically reduced infectivity, revealing the importance of glycosylation for viral infectivity. Interestingly, N234Q was markedly resistant to neutralizing antibodies, whereas N165Q became more sensitive. These findings could be of value in the development of vaccine and therapeutic antibodies.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0404511

Journal ID (pubmed-jr-id): 7473

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Nihms-submitted: 25 December 2020

Publication date (Electronic): 12 November 2020

Publication date (Print): 18 December 2020

Publication date PMC-release: 01 January 2021

Volume: 370

Issue: 6523

Pages: 1464-1468

Affiliations

[1 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

[2 ]Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

[3 ]Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan ^.

[4 ]Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA

[5 ]Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

[6 ]Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan

[7 ]Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Author notes

[§]

These authors contribute equally.

Author contribution: YJH, YK and RSB conceived the study; YJH, SC, PH, CE and LEG performed most of the experiments; MK, KHD iii, SRL and AS assisted animal experiments; REL, TMK, RG, CEE assisted in vitro experiments; NN, KT and TS performed histological analyses; LVT, KO, AJM, LB, ADS, DMM, RCB and SHR provided essential materials and reagents; YK, RSB, PH and LEG supervised the research; YJH wrote the manuscript and generated the illustrations; YK, RSB reviewed and edited the manuscript. All authors read and approved the final manuscript.

[* ]Address correspondence to: Yoshihiro Kawaoka, yoshihiro.kawaoka@ 123456wisc.edu ; Ralph S. Baric, rbaric@ 123456email.unc.edu

Article

Manuscript ID: NIHMS1649512

DOI: 10.1126/science.abe8499

PMC ID: 7775736

PubMed ID: 33184236

SO-VID: 314bb505-272e-41e7-a580-6617c478f5ff

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This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

SARS-CoV-2 D614G Variant Exhibits Efficient Replication ex vivo and Transmission in vivo

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Novel Coronavirus Disease COVID-19

Most cited references 23

Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity

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