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SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity.
Nat Commun. 2021 02 08; 12(1):848.NC

Abstract

The causative agent of the COVID-19 pandemic, SARS-CoV-2, is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the ACE2 receptor and is cleaved by TMPRSS2. However, whether S mutations affect SARS-CoV-2 cell entry remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than that of SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural and binding analyses. Nevertheless, the D614G mutation does not affect neutralization by antisera against prototypic viruses. Taken together, we conclude that the D614G mutation increases cell entry by acquiring higher affinity to ACE2 while maintaining neutralization susceptibility. Based on these findings, further worldwide surveillance is required to understand SARS-CoV-2 transmissibility among humans.

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Publisher Full Text
ncbi.nlm.nih.gov
doi.org
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Authors+Show Affiliations

Ozono S
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan.
Zhang Y
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Ode H
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.
Sano K
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Tan TS
Division of Infection and Immunity, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
Imai K
Self-Defense Forces Central Hospital, Tokyo, Japan.
Miyoshi K
Self-Defense Forces Central Hospital, Tokyo, Japan.
Kishigami S
Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan.
Ueno T
Division of Infection and Immunity, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
Iwatani Y
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.
Suzuki T
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Tokunaga K
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. tokunaga@nih.go.jp.

MeSH

Angiotensin-Converting Enzyme 2Binding, CompetitiveCOVID-19HumansModels, MolecularMutationPandemicsProtein BindingProtein DomainsReceptors, VirusSARS-CoV-2Serine EndopeptidasesSpike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33558493

Citation

Ozono, Seiya, et al. "SARS-CoV-2 D614G Spike Mutation Increases Entry Efficiency With Enhanced ACE2-binding Affinity." Nature Communications, vol. 12, no. 1, 2021, p. 848.
Ozono S, Zhang Y, Ode H, et al. SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nat Commun. 2021;12(1):848.
Ozono, S., Zhang, Y., Ode, H., Sano, K., Tan, T. S., Imai, K., Miyoshi, K., Kishigami, S., Ueno, T., Iwatani, Y., Suzuki, T., & Tokunaga, K. (2021). SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nature Communications, 12(1), 848. https://doi.org/10.1038/s41467-021-21118-2
Ozono S, et al. SARS-CoV-2 D614G Spike Mutation Increases Entry Efficiency With Enhanced ACE2-binding Affinity. Nat Commun. 2021 02 8;12(1):848. PubMed PMID: 33558493.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. AU - Ozono,Seiya, AU - Zhang,Yanzhao, AU - Ode,Hirotaka, AU - Sano,Kaori, AU - Tan,Toong Seng, AU - Imai,Kazuo, AU - Miyoshi,Kazuyasu, AU - Kishigami,Satoshi, AU - Ueno,Takamasa, AU - Iwatani,Yasumasa, AU - Suzuki,Tadaki, AU - Tokunaga,Kenzo, Y1 - 2021/02/08/ PY - 2020/07/03/received PY - 2021/01/14/accepted PY - 2021/2/9/entrez PY - 2021/2/10/pubmed PY - 2021/2/23/medline SP - 848 EP - 848 JF - Nature communications JO - Nat Commun VL - 12 IS - 1 N2 - The causative agent of the COVID-19 pandemic, SARS-CoV-2, is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the ACE2 receptor and is cleaved by TMPRSS2. However, whether S mutations affect SARS-CoV-2 cell entry remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than that of SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural and binding analyses. Nevertheless, the D614G mutation does not affect neutralization by antisera against prototypic viruses. Taken together, we conclude that the D614G mutation increases cell entry by acquiring higher affinity to ACE2 while maintaining neutralization susceptibility. Based on these findings, further worldwide surveillance is required to understand SARS-CoV-2 transmissibility among humans. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/33558493/SARS_CoV_2_D614G_spike_mutation_increases_entry_efficiency_with_enhanced_ACE2_binding_affinity_ L2 - https://doi.org/10.1038/s41467-021-21118-2 DB - PRIME DP - Unbound Medicine ER -