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

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.

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.

Metrics

  • 12,472
    views
  • 949
    downloads
  • 184
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Zharko Daniloski
  2. Tristan X Jordan
  3. Juliana K Ilmain
  4. Xinyi Guo
  5. Gira Bhabha
  6. Benjamin R tenOever
  7. Neville E Sanjana
(2021)
The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types
eLife 10:e65365.
https://doi.org/10.7554/eLife.65365

Share this article

https://doi.org/10.7554/eLife.65365

Further reading

    1. Epidemiology and Global Health
    Yuan Zhang, Dan Tang ... Xing Zhao
    Research Article

    Background:

    Biological aging exhibits heterogeneity across multi-organ systems. However, it remains unclear how is lifestyle associated with overall and organ-specific aging and which factors contribute most in Southwest China.

    Methods:

    This study involved 8396 participants who completed two surveys from the China Multi-Ethnic Cohort (CMEC) study. The healthy lifestyle index (HLI) was developed using five lifestyle factors: smoking, alcohol, diet, exercise, and sleep. The comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera–Doubal method based on longitudinal clinical laboratory measurements, and validation were conducted to select BA reflecting related diseases. Fixed effects model was used to examine the associations between HLI or its components and the acceleration of validated BAs. We further evaluated the relative contribution of lifestyle components to comprehension and organ systems BAs using quantile G-computation.

    Results:

    About two-thirds of participants changed HLI scores between surveys. After validation, three organ-specific BAs (the cardiopulmonary, metabolic, and liver BAs) were identified as reflective of specific diseases and included in further analyses with the comprehensive BA. The health alterations in HLI showed a protective association with the acceleration of all BAs, with a mean shift of –0.19 (95% CI −0.34, –0.03) in the comprehensive BA acceleration. Diet and smoking were the major contributors to overall negative associations of five lifestyle factors, with the comprehensive BA and metabolic BA accounting for 24% and 55% respectively.

    Conclusions:

    Healthy lifestyle changes were inversely related to comprehensive and organ-specific biological aging in Southwest China, with diet and smoking contributing most to comprehensive and metabolic BA separately. Our findings highlight the potential of lifestyle interventions to decelerate aging and identify intervention targets to limit organ-specific aging in less-developed regions.

    Funding:

    This work was primarily supported by the National Natural Science Foundation of China (Grant No. 82273740) and Sichuan Science and Technology Program (Natural Science Foundation of Sichuan Province, Grant No. 2024NSFSC0552). The CMEC study was funded by the National Key Research and Development Program of China (Grant No. 2017YFC0907305, 2017YFC0907300). The sponsors had no role in the design, analysis, interpretation, or writing of this article.

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    Bo Zheng, Bronner P Gonçalves ... Caoyi Xue
    Research Article

    Background:

    In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.

    Methods:

    We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).

    Results:

    275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.

    Conclusions:

    In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.

    Funding:

    This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).