D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Viral Transmission via Enhanced Furin-mediated Spike Cleavage

  1. Ya-Wen Cheng
  2. Tai-Ling Chao
  3. Chiao-Ling Li
  4. Sheng-Han Wang
  5. Han-Chieh Kao
  6. Ya-Min Tsai
  7. Hurng-Yi Wang
  8. Chi-Ling Hsieh
  9. Pei-Jer Chen
  10. Sui-Yuan Chang
  11. Shiou-Hwei Yeh

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Abstract

Since the D614G substitution in the spike (S) of SARS-CoV-2 emerged, the variant strain underwent rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage of viral spreading. To explore the mechanism, we analyzed 18 viral isolates containing S proteins with either G614 or D614. Both the virus titer and syncytial phenotype were significantly increased in S-G614 than in S-D614 isolates. We further showed increased cleavage of S at the furin substrate site, a key event that promotes syncytium, in S-G614 isolates. These functions of the D614G substitution were validated in cells expressing S protein. The effect on syncytium was abolished by furin inhibitor treatment and mutation of the furin-cleavage site, suggesting its dependence on cleavage by furin. Our study provides a mechanistic explanation for the increased transmissibility of S-G614 containing SARS-CoV-2 through enhanced furin-mediated S cleavage, which increases membrane fusion and virus infectivity.

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    SciScore for 10.1101/2021.01.27.428541: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

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    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

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  2. Version published to 10.1101/2021.01.27.428541 on bioRxiv