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SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity

Author

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  • Seiya Ozono

    (National Institute of Infectious Diseases
    University of Yamanashi)

  • Yanzhao Zhang

    (National Institute of Infectious Diseases)

  • Hirotaka Ode

    (National Hospital Organization Nagoya Medical Center)

  • Kaori Sano

    (National Institute of Infectious Diseases)

  • Toong Seng Tan

    (Joint Research Center for Human Retrovirus Infection)

  • Kazuo Imai

    (Self-Defense Forces Central Hospital)

  • Kazuyasu Miyoshi

    (Self-Defense Forces Central Hospital)

  • Satoshi Kishigami

    (University of Yamanashi)

  • Takamasa Ueno

    (Joint Research Center for Human Retrovirus Infection)

  • Yasumasa Iwatani

    (National Hospital Organization Nagoya Medical Center)

  • Tadaki Suzuki

    (National Institute of Infectious Diseases)

  • Kenzo Tokunaga

    (National Institute of Infectious Diseases)

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.

Suggested Citation

  • Seiya Ozono & Yanzhao Zhang & Hirotaka Ode & Kaori Sano & Toong Seng Tan & Kazuo Imai & Kazuyasu Miyoshi & Satoshi Kishigami & Takamasa Ueno & Yasumasa Iwatani & Tadaki Suzuki & Kenzo Tokunaga, 2021. "SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21118-2
    DOI: 10.1038/s41467-021-21118-2
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    1. Tomokazu Tamura & Takashi Irie & Sayaka Deguchi & Hisano Yajima & Masumi Tsuda & Hesham Nasser & Keita Mizuma & Arnon Plianchaisuk & Saori Suzuki & Keiya Uriu & Mst Monira Begum & Ryo Shimizu & Michae, 2024. "Virological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
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    4. Matthew R. Chang & Luke Tomasovic & Natalia A. Kuzmina & Adam J. Ronk & Patrick O. Byrne & Rebecca Johnson & Nadia Storm & Eduardo Olmedillas & Yixuan J. Hou & Alexandra Schäfer & Sarah R. Leist & Lon, 2022. "IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Mai Komori & Takuto Nogimori & Amber L. Morey & Takashi Sekida & Keiko Ishimoto & Matthew R. Hassett & Yuji Masuta & Hirotaka Ode & Tomokazu Tamura & Rigel Suzuki & Jeff Alexander & Yasutoshi Kido & K, 2023. "saRNA vaccine expressing membrane-anchored RBD elicits broad and durable immunity against SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Ryuta Uraki & Shun Iida & Peter J. Halfmann & Seiya Yamayoshi & Yuichiro Hirata & Kiyoko Iwatsuki-Horimoto & Maki Kiso & Mutsumi Ito & Yuri Furusawa & Hiroshi Ueki & Yuko Sakai-Tagawa & Makoto Kuroda , 2023. "Characterization of SARS-CoV-2 Omicron BA.2.75 clinical isolates," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Hisano Yajima & Yuki Anraku & Yu Kaku & Kanako Terakado Kimura & Arnon Plianchaisuk & Kaho Okumura & Yoshiko Nakada-Nakura & Yusuke Atarashi & Takuya Hemmi & Daisuke Kuroda & Yoshimasa Takahashi & Shu, 2024. "Structural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Yu, Zhenhua & Arif, Robia & Fahmy, Mohamed Abdelsabour & Sohail, Ayesha, 2021. "Self organizing maps for the parametric analysis of COVID-19 SEIRS delayed model," Chaos, Solitons & Fractals, Elsevier, vol. 150(C).
    9. Alexander J. Pak & Alvin Yu & Zunlong Ke & John A. G. Briggs & Gregory A. Voth, 2022. "Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Pengcheng Han & Chao Su & Yanfang Zhang & Chongzhi Bai & Anqi Zheng & Chengpeng Qiao & Qing Wang & Sheng Niu & Qian Chen & Yuqin Zhang & Weiwei Li & Hanyi Liao & Jing Li & Zengyuan Zhang & Heecheol Ch, 2021. "Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    11. Tamara Kaleta & Lisa Kern & Samuel Leandro Hong & Martin Hölzer & Georg Kochs & Julius Beer & Daniel Schnepf & Martin Schwemmle & Nena Bollen & Philipp Kolb & Magdalena Huber & Svenja Ulferts & Sebast, 2022. "Antibody escape and global spread of SARS-CoV-2 lineage A.27," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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