Skip to main content
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2021 Feb 4;64(7):1062–1067. doi: 10.1007/s11427-020-1893-9

Making sense of spike D614G in SARS-CoV-2 transmission

Aria C Shi 1, Xuping Xie 2,
PMCID: PMC7882856  PMID: 33587268

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the current coronavirus disease 2019 (COVID-19) pandemic, has evolved to adapt to human host and transmission over the past 12 months. One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein (D614G), which has become dominant in the currently circulating virus strains. Since spike protein determines host ranges, tissue tropism, and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2 (ACE2), the D614G mutation is hypothesized to enhance viral fitness in human host, leading to increased transmission during the global pandemic. Here we summarize the recent progress on the role of the D614G mutation in viral replication, pathogenesis, transmission, and vaccine and therapeutic antibody development. These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.

Keywords: SARS-CoV-2, D614G, COVID-19

Acknowledgements

We thank colleagues for helpful discussion during this study.

Footnotes

Compliance and ethics

The author(s) declare that they have no conflict of interest.

References

  1. Chan, J.F.W., Zhang, A.J., Yuan, S., Poon, V.K.M., Chan, C.C.S., Lee, A.C. Y., Chan, W. M., Fan, Z., Tsoi, H. W., Wen, L., et al. (2020). Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) in a Golden Syrian Hamster Model: implications for disease pathogenesis and transmissibility. Clin Infect Dis, doi: 10.1093/cid/ciaa325. [DOI] [PMC free article] [PubMed]
  2. Dai, L., and Gao, G.F. (2020). Viral targets for vaccines against COVID-19. Nat Rev Immunol, doi: 10.1038/s41577-020-00480-0. [DOI] [PMC free article] [PubMed]
  3. Daniloski, Z., Guo, X., and Sanjana, N.E. (2020). The D614G mutation in SARS-CoV-2 Spike increases transduction of multiple human cell types. bioRxiv, doi: 10.1101/2020.06.14.151357. [DOI] [PMC free article] [PubMed]
  4. Davies, N.G., Barnard, R.C., Jarvis, C.I., Kucharski, A.J., Munday, J., Pearson, C.A.B., Russell, T.W., Tully, D.C., Abbott, S., Gimma, A., et al. (2020). Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medRxiv, doi: 10.1101/2020.12.24.20248822.
  5. Hou, Y.J., Chiba, S., Halfmann, P., Ehre, C., Kuroda, M., Dinnon Iii, K.H., Leist, S.R., Schäfer, A., Nakajima, N., Takahashi, K., et al. (2020a). SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science eabe8499. [DOI] [PMC free article] [PubMed]
  6. Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon Iii KH, Kato T, Lee RE, Yount BL, Mascenik TM, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182:429–446. doi: 10.1016/j.cell.2020.05.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Imai M, Iwatsuki-Horimoto K, Hatta M, Loeber S, Halfmann PJ, Nakajima N, Watanabe T, Ujie M, Takahashi K, Ito M, et al. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc Natl Acad Sci USA. 2020;117:16587–16595. doi: 10.1073/pnas.2018975117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jaimes, J., Millet, J., and Whittaker, G. (2020). Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 site. SSRN J, doi: 10.2139/ssrn.3581359. [DOI] [PMC free article] [PubMed]
  10. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell. 2020;182:812–827. doi: 10.1016/j.cell.2020.06.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lorenzo-Redondo, R., Nam, H.H., Roberts, S.C., Simons, L.M., Jennings, L.J., Qi, C., Achenbach, C.J., Hauser, A.R., Ison, M.G., Hultquist, J.F., et al. (2020). A unique clade of SARS-CoV-2 viruses is associated with lower viral loads in patient upper airways. medRxiv, doi: 10.1101/2020.05.19.20107144. [DOI] [PMC free article] [PubMed]
  12. Muruato AE, Fontes-Garfias CR, Ren P, Garcia-Blanco MA, Menachery VD, Xie X, Shi PY. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nat Commun. 2020;11:4059. doi: 10.1038/s41467-020-17892-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Omotuyi IO, Nash O, Ajiboye OB, Iwegbulam CG, Oyinloye EB, Oyedeji OA, Kashim ZA, Okaiyeto K. Atomistic simulation reveals structural mechanisms underlying D614G spike glycoprotein-enhanced fitness in SARS-CoV-2. J Comput Chem. 2020;41:2158–2161. doi: 10.1002/jcc.26383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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. (2020). Spike mutation D614G alters SARS-CoV-2 fitness. Nature, doi: 10.1038/s41586-020-2895-3. [DOI] [PMC free article] [PubMed]
  15. Rambaut, A., Loman, N., Pybus, O., Barclay, W., Barrett, J., Carabelli, A., Connor, T., Peacock, T., Robertson, D.L., Volz, E. (2020). Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Virological, https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563.
  16. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, Li F. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA. 2020;117:11727–11734. doi: 10.1073/pnas.2003138117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 2013;9:e1003565. doi: 10.1371/journal.ppat.1003565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Tegally, H., Wilkinson, E., Giovanetti, M., Iranzadeh, A., Fonseca, V., Giandhari, J., Doolabh, D., Pillay, S., San, E.J., Wibmer, K., et al. (2020). Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, doi: 10.1101/2020.12.21.20248640.
  19. Walsh EE, Frenck RW, Jr., Falsey AR, Kitchin N, Absalon J, Gurtman A, Lockhart S, Neuzil K, Mulligan MJ, Bailey R, et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N Engl J Med. 2020;383:2439–2450. doi: 10.1056/NEJMoa2027906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Wang C, Liu Z, Chen Z, Huang X, Xu M, He T, Zhang Z. The establishment of reference sequence for SARS-CoV-2 and variation analysis. J Med Virol. 2020;92:667–674. doi: 10.1002/jmv.25762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Weissman D, Alameh MG, de Silva T, Collini P, Hornsby H, Brown R, LaBranche CC, Edwards RJ, Sutherland L, Santra S, et al. D614G spike mutation increases SARS CoV-2 susceptibility to neutralization. Cell Host Microbe. 2020;29:23–31. doi: 10.1016/j.chom.2020.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Xie X, Muruato A, Lokugamage KG, Narayanan K, Zhang X, Zou J, Liu J, Schindewolf C, Bopp NE, Aguilar PV, et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe. 2020;27:841–848. doi: 10.1016/j.chom.2020.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Xie, X., Zou, J., Fontes-Garfias, C.R., Xia, H., Swanson, K.A., Cutler, M., Cooper, D., Menachery, V.D., Weaver, S., Dormitzer, P.R., et al. (2021). Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera. Res Sq, rs.3.rs-143532.
  24. Yurkovetskiy L, Wang X, Pascal KE, Tomkins-Tinch C, Nyalile TP, Wang Y, Baum A, Diehl WE, Dauphin A, Carbone C, et al. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell. 2020;183:739–751. doi: 10.1016/j.cell.2020.09.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zhang, L., Jackson, C.B., Mou, H., Ojha, A., Rangarajan, E.S., Izard, T., Farzan, M., Choe, H. (2020). The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. bioRxiv, doi: 10.1101/2020.06.12.148726.
  26. Zhou, B., Thao, T.T.N., Hoffmann, D., Taddeo, A., Ebert, N., Labroussaa, F., Pohlmann, A., King, J., Portmann, J., Halwe, N.J., et al. (2020a). SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility. bioRxiv, doi: 10.1101/2020.10.27.357558.
  27. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi: 10.1038/s41586-020-2012-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Science China. Life Sciences are provided here courtesy of Nature Publishing Group

RESOURCES