1. Epidemiology and Global Health
  2. Microbiology and Infectious Disease
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The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types

  1. Zharko Daniloski
  2. Tristan X Jordan
  3. Juliana K Ilmain
  4. Xinyi Guo
  5. Gira Bhabha
  6. Benjamin R tenOever  Is a corresponding author
  7. Neville E Sanjana  Is a corresponding author
  1. New York Genome Center, United States
  2. Icahn School of Medicine at Mount Sinai, United States
  3. New York University School of Medicine, United States
Research Article
  • Cited 49
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Cite this article as: eLife 2021;10:e65365 doi: 10.7554/eLife.65365

Abstract

A novel variant of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis on wild-type human codon optimized Spike to introduce the D614G variant. Using multiple human cell lines, including human lung epithelial cells, we found that the lentiviral particles pseudotyped with Spike D614G are more effective at transducing cells than ones pseudotyped with wild-type Spike. The increased transduction with Spike D614G ranged from 1.3 to 2.4-fold in Caco-2 and Calu-3 cells expressing endogenous ACE2, and 1.5 to 7.7-fold in A549ACE2 and Huh7.5ACE2 overexpressing ACE2. Furthermore, trans-complementation of SARS-CoV-2 virus with Spike D614G showed an increased infectivity of human cells. Although there is minimal difference in ACE2 receptor binding between the D614 and G614 Spike variants, we show that the G614 variant is more resistant to proteolytic cleavage in human cells, suggesting a possible mechanism for the increased transduction.

Data availability

All data generated or analyzed in this study are included in this published article and its supplementary information files. The Spike D614G expression plasmid has been deposited to Addgene (#166850).

The following previously published data sets were used

Article and author information

Author details

  1. Zharko Daniloski

    New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.
  2. Tristan X Jordan

    Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  3. Juliana K Ilmain

    Cell Biology, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9507-5069
  4. Xinyi Guo

    New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.
  5. Gira Bhabha

    Department of Cell Biology, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0624-6178
  6. Benjamin R tenOever

    Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    benjamin.tenoever@mssm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0324-3078
  7. Neville E Sanjana

    New York Genome Center, New York, United States
    For correspondence
    neville@sanjanalab.org
    Competing interests
    Neville E Sanjana, N.E.S. is an advisor to Vertex..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1504-0027

Funding

American Heart Association (20POST35220040)

  • Zharko Daniloski

Sidney Kimmel Foundation

  • Neville E Sanjana

National Institute of Allergy and Infectious Diseases (R01AI123155)

  • Tristan X Jordan

Pew Charitable Trusts (PEW-00033055)

  • Gira Bhabha

Searle Scholars Program (SSP-2018-2737)

  • Gira Bhabha

National Institute of Allergy and Infectious Diseases (R01AI147131)

  • Gira Bhabha

Defense Advanced Research Projects Agency (HR0011-20-2-0040)

  • Benjamin R tenOever

National Human Genome Research Institute (DP2HG010099)

  • Neville E Sanjana

National Cancer Institute (R01CA218668)

  • Neville E Sanjana

Defense Advanced Research Projects Agency (D18AP00053)

  • Neville E Sanjana

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank Kirchhoff, Ulm University Medical Center, Germany

Publication history

  1. Received: December 2, 2020
  2. Accepted: February 10, 2021
  3. Accepted Manuscript published: February 11, 2021 (version 1)
  4. Version of Record published: February 18, 2021 (version 2)

Copyright

© 2021, Daniloski et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Further reading

Further reading

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    Wuqing Huang et al.
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    Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors and NPC1L1 inhibitior) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study.

    Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including eQTLs of drugs target genes, and genetic variants within or nearby drugs target genes associated with LDL cholesterol from GWAS. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates.

    Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74). No consistent evidence from both analyses was found for other associations.

    Conclusions: This 2-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization.

    Funding: Fujian Province Major Science and Technology Program.

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