SARS-CoV-2 spike D614G change enhances replication and transmission
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Abstract
During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic 1. However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo-particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating.
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The B.1.1.7, B.1.351, and P.1 lineages all harbor a N501Y mutation in the RBD, which increases the affinity for the ACE2 receptor, and a D614G mutation, which increases virion spike density, infectivity, and transmissibility.
“The B.1.1.7, B.1.351, and P.1 lineages all harbor a N501Y mutation in the RBD, which increases the affinity for the ACE2 receptor (57, 58), and a D614G mutation, which increases virion spike density, infectivity, and transmissibility (59, 60).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [60]
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Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884 · see citing works
A novel coronavirus from patients with pneumonia in China, 2019
Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2001017 · Cited by 28,244 · see citing works
A pneumonia outbreak associated with a new coronavirus of probable bat origin
Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., Huang, C.-L., et al. (2020) · Nature · doi:10.1038/s41586-020-2012-7 · Cited by 21,969 · see citing works
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286 · see citing works
A new coronavirus associated with human respiratory disease in China
Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., Hu, Y., Tao, Z.-W., Tian, J.-H., Pei, Y.-Y., et al. (2020) · Nature · doi:10.1038/s41586-020-2008-3 · Cited by 11,688 · see citing works
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., Graham, B. S., & McLellan, J. S. (2020) · Science · doi:10.1126/science.abb2507 · Cited by 8,897 · see citing works
Korber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E. E., Bhattacharya, T., Foley, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.043 · Cited by 4,281 · see citing works
Letko, M., Marzi, A., & Munster, V. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0688-y · Cited by 3,109 · see citing works
Spike mutation D614G alters SARS-CoV-2 fitness
Plante, J. A., Liu, Y., Liu, J., Xia, H., Johnson, B. A., Lokugamage, K. G., Zhang, X., Muruato, A. E., Zou, J., Fontes-Garfias, C. R., et al. (2021) · Nature · doi:10.1038/s41586-020-2895-3 · Cited by 1,558 · see citing works
The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity
Li, Q., Wu, J., Nie, J., Zhang, L., Hao, H., Liu, S., Zhao, C., Zhang, Q., Liu, H., Nie, L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.012 · Cited by 1,420 · see citing works
Pathogenesis and transmission of SARS-CoV-2 in golden hamsters
Sia, S. F., Yan, L.-M., Chin, A. W. H., Fung, K., Choy, K.-T., Wong, A. Y. L., Kaewpreedee, P., Perera, R. A. P. M., Poon, L. L. M., Nicholls, J. M., et al. (2020) · Nature · doi:10.1038/s41586-020-2342-5 · Cited by 1,303 · see citing works
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice
Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2312-y · Cited by 1,126 · see citing works
Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
Yurkovetskiy, L., Wang, X., Pascal, K. E., Tomkins-Tinch, C., Nyalile, T. P., Wang, Y., Baum, A., Diehl, W. E., Dauphin, A., Carbone, C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.032 · Cited by 1,025 · see citing works
Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion ConformationPreprint
Wrapp, D., Wang, N., Corbett, K. S., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.11.944462 · Cited by 1,010 · see citing works
Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development
Imai, M., Iwatsuki‐Horimoto, K., Hatta, M., Loeber, S. J., Halfmann, P., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009799117 · Cited by 977 · see citing works
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo
Hou, Y. J., Chiba, S., Halfmann, P., Ehre, C., Kuroda, M., Dinnon, K. H., Leist, S. R., Schäfer, A., Nakajima, N., Takahashi, K., et al. (2020) · Science · doi:10.1126/science.abe8499 · Cited by 900 · see citing works
Infection and Rapid Transmission of SARS-CoV-2 in Ferrets
Kim, Y., Kim, S.-G., Kim, S.-M., Kim, E.-H., Park, S.-J., Yu, K.-M., Chang, J.-H., Kim, E. J., Lee, S., Casel, M. A. B., et al. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.03.023 · Cited by 883 · see citing works
Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2
Jiang, R.-D., Liu, M.-Q., Chen, Y., Shan, C., Zhou, Y.-W., Shen, X.-R., Li, Q., Zhang, L., Zhu, Y., Si, H.-R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.027 · Cited by 541 · see citing works
Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform
Thao, T. T. N., Labroussaa, F., Ebert, N., V’kovski, P., Stalder, H., Portmann, J., Kelly, J. N., Steiner, S., Holwerda, M., Kratzel, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2294-9 · Cited by 485 · see citing works
Self-citationSARS-CoV-2 is transmitted via contact and via the air between ferrets
Richard, M., Kok, A., de Meulder, D., Bestebroer, T. M., Lamers, M. M., Okba, N. M. A., van Vlissingen, M. F., Rockx, B., Haagmans, B. L., Koopmans, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17367-2 · Cited by 438 · see citing works
Thiel, V., Herold, J., Schelle, B., & Siddell, S. G. (2001) · Journal of General Virology · doi:10.1099/0022-1317-82-6-1273 · Cited by 296 · see citing works
Self-citationAge-Dependent Progression of SARS-CoV-2 Infection in Syrian Hamsters
Osterrieder, N., Bertzbach, L. D., Dietert, K., Abdelgawad, A., Vladimirova, D., Kunec, D., Hoffmann, D., Beer, M., Gruber, A. D., & Trimpert, J. (2020) · Viruses · doi:10.3390/v12070779 · Cited by 218 · see citing works
Self-citationViral deep sequencing needs an adaptive approach: IRMA, the iterative refinement meta-assembler
Shepard, S. S., Meno, S., Bahl, J., Wilson, M. M., Barnes, J., & Neuhaus, E. B. (2016) · BMC Genomics · doi:10.1186/s12864-016-3030-6 · Cited by 212 · see citing works
Self-citationReverse Genetics of SARS-Related Coronavirus Using Vaccinia Virus-Based Recombination
van den Worm, S. H. E., Eriksson, K., Zevenhoven-Dobbe, J. C., Weber, F., Züst, R., Kuri, T., Dijkman, R., Chang, G., Siddell, S. G., Snijder, E. J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032857 · Cited by 106 · see citing works
Self-citationAlouane, T., Laamarti, M., Essabbar, A., Hakmi, M., Bouricha, E. M., Chemao-Elfihri, M. W., Kartti, S., Boumajdi, N., Bendani, H., Laamarti, R., et al. (2020) · Pathogens · doi:10.3390/pathogens9100829 · Cited by 106 · see citing works
Imai, H., Uchiumi, T., & Kodera, N. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2018975117 · Cited by 88 · see citing works
SARS-CoV-2 is transmitted via contact and via the air between ferretsPreprint
Richard, M., Kok, A., de Meulder, D., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.16.044503 · Cited by 66 · see citing works
Age-dependent progression of SARS-CoV-2 infection in Syrian hamstersPreprint
Osterrieder, N., Bertzbach, L. D., Dietert, K., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.10.144188 · Cited by 66 · see citing works
Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platformPreprint
Thao, T. T. N., Labroussaa, F., Ebert, N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.21.959817 · Cited by 65 · see citing works
Self-citationcatseyes: Create Catseye Plots Illustrating the Normal Distribution of the Means
Andersen, C. (2019) · doi:10.32614/cran.package.catseyes · Cited by 17 · see citing works
Andersen, C. R. (2020) · Cited by 2 · see citing works
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Hoffmann, M., Krüger, N., Schulz, S., Cossmann, A., Rocha, C., Kempf, A., Nehlmeier, I., Graichen, L., Moldenhauer, A.-S., Winkler, M. S., et al. (2022) · Cell · doi:10.1016/j.cell.2021.12.032 · Cited by 889 · see citing works
Deng, X., Garcia-Knight, M. A., Khalid, M. M., Servellita, V., Wang, C., Morris, M. K., Sotomayor-González, A., Glasner, D. R., Reyes, K. R., Gliwa, A. S., et al. (2021) · doi:10.1101/2021.03.07.21252647 · Cited by 651 · see citing works
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Zeng, C., Evans, J. P., King, T., Zheng, Y.-M., Oltz, E. M., Whelan, S. P. J., Saif, L. J., Peeples, M. E., & Liu, S.-L. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111400119 · Cited by 246 · see citing works
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Liu, Y., Liu, J., Plante, K. S., Plante, J. A., Xie, X., Zhang, X., Ku, Z., An, Z., Scharton, D., Schindewolf, C., et al. (2021) · doi:10.1101/2021.03.08.434499 · Cited by 574 · see citing works
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- Authors
- Zhou, B., Thao, T. T. N., Hoffmann, D., Taddeo, A., Ebert, N., Labroussaa, F., Pohlmann, A., King, J., Steiner, S., Kelly, J. N., Portmann, J., Halwe, N. J., Ulrich, L., Trüeb, B. S., Fan, X., Hoffmann, B., Wang, L., Thomann, L., Lin, X., Stalder, H., Pozzi, B., de Brot, S., Jiang, N., Cui, D., Hossain, J., Wilson, M. M., Keller, M. W., Stark, T. J., Barnes, J. R., Dijkman, R., Jores, J., Benarafa, C., Wentworth, D. E., Thiel, V., & Beer, M.
- Affiliations
- Centers for Disease Control and Prevention (US)
- University of Bern (CH)
- Friedrich-Loeffler-Institut (DE)
- Battelle (US)
- Oak Ridge Institute for Science and Education (US)
- Corresponding author
- Benarafa, Charaf
- Wentworth, David E.
- Thiel, Volker
- Beer, Martin
- ORCID
- Zhou, Bin
- Thao, Tran Thi Nhu
- Hoffmann, Donata
- Taddeo, Adriano
- Ebert, Nadine
- Labroussaa, Fabien
- Pohlmann, Anne
- King, Jacqueline
- Steiner, Silvio
- Kelly, Jenna N.
- Halwe, Nico Joel
- Ulrich, Lorenz
- Trüeb, Bettina Salome
- Fan, Xiaoyu
- Hoffmann, Bernd
- Wang, Li
- Thomann, Lisa
- Lin, Xudong
- Stalder, Hanspeter
- Pozzi, Berta
- Jiang, Nannan
- Cui, Dan
- Hossain, Jaber
- Wilson, Malania M.
- Keller, Matthew W.
- Barnes, John R.
- Dijkman, Ronald
- Jores, Joerg
- Benarafa, Charaf
- Wentworth, David E.
- Thiel, Volker
- Beer, Martin
- Venue
- Nature
- Published
- 2021-02-26
- Volume
- 592
- Issue
- 7852
- Pages
- 122-127
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7605563
- OpenAlex
- W3129399011
- Cited by
- 538
- References
- 31
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 57 · 2023: 82 · 2022: 161 · 2021: 185 · 2020: 6
- FWCI
- 38.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- OpenAgrar (submittedVersion)
- Funders
- National Science Foundation (874735)
- University of Bern
- European Commission (721367, 874735, HORIZON2020, COVID-19)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (173085, 196644, 196062, 310030)
- Bundesamt für Gesundheit
- Bundesministerium für Bildung und Forschung (01KI1723A)
- Bundesministerium für Ernährung und Landwirtschaft (874735)
- National Institutes of Health (874735, COVID-19)
- Centers for Disease Control and Prevention
- National Institute of Allergy and Infectious Diseases (P01AI059576, COVID-19, 874735, U54AI057158)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, spike protein, ACE2 binding, viral fitness, virus transmission, viral replication, founder effect, hamster model, ferret model, COVID-19 pandemic
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