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SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances viral fusogenicity and pathogenicity

View ORCID ProfileAkatsuki Saito, Takashi Irie, Rigel Suzuki, Tadashi Maemura, View ORCID ProfileHesham Nasser, Keiya Uriu, Yusuke Kosugi, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, View ORCID ProfileJumpei Ito, Jiaqi Wu, Kiyoko Iwatsuki-Horimoto, Mutsumi Ito, Seiya Yamayoshi, Seiya Ozono, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Kumiko Yoshimatsu, Ryoko Kawabata, Takemasa Sakaguchi, View ORCID ProfileKenzo Tokunaga, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kazuhisa Yoshimura, Akifumi Takaori-Kondo, Masaki Imai, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, Takasuke Fukuhara, Yoshihiro Kawaoka, View ORCID ProfileKei Sato
doi: https://doi.org/10.1101/2021.06.17.448820
Akatsuki Saito
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
2Center for Animal Disease Control, University of Miyazaki, Miyazaki 8892192, Japan
3Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 8892192, Japan
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  • ORCID record for Akatsuki Saito
Takashi Irie
4Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Rigel Suzuki
5Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido 0608638, Japan
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Tadashi Maemura
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
7Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, WI 53711, USA
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Hesham Nasser
8Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
9Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41511, Egypt
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Keiya Uriu
10Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Yusuke Kosugi
10Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Kotaro Shirakawa
11Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Kenji Sadamasu
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Izumi Kimura
10Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Jumpei Ito
10Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Jiaqi Wu
13Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 2591193, Japan
14CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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Kiyoko Iwatsuki-Horimoto
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
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Mutsumi Ito
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
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Seiya Yamayoshi
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
15The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 1628655, Japan
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Seiya Ozono
16Department of Pathology, National Institute of Infectious Diseases, Tokyo 1628640, Japan
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Erika P Butlertanaka
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
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Yuri L Tanaka
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
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Ryo Shimizu
8Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
17Graduate School of Medical Sciences, Kumamoto University, Kumamoto 8600811, Japan
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Kenta Shimizu
5Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido 0608638, Japan
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Kumiko Yoshimatsu
18Institute for Genetic Medicine, Hokkaido University, Hokkaido 0600815, Japan
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Ryoko Kawabata
4Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Takemasa Sakaguchi
4Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Kenzo Tokunaga
16Department of Pathology, National Institute of Infectious Diseases, Tokyo 1628640, Japan
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Isao Yoshida
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Hiroyuki Asakura
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Mami Nagashima
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Yasuhiro Kazuma
11Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Ryosuke Nomura
11Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Yoshihito Horisawa
11Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Kazuhisa Yoshimura
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Akifumi Takaori-Kondo
11Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Masaki Imai
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
15The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 1628655, Japan
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So Nakagawa
13Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 2591193, Japan
14CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp fukut@pop.med.hokudai.ac.jp yoshihiro.kawaoka@wisc.edu KeiSato@g.ecc.u-tokyo.ac.jp
Terumasa Ikeda
8Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp fukut@pop.med.hokudai.ac.jp yoshihiro.kawaoka@wisc.edu KeiSato@g.ecc.u-tokyo.ac.jp
Takasuke Fukuhara
5Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido 0608638, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp fukut@pop.med.hokudai.ac.jp yoshihiro.kawaoka@wisc.edu KeiSato@g.ecc.u-tokyo.ac.jp
Yoshihiro Kawaoka
6Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo 1088639, Japan
7Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, WI 53711, USA
15The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 1628655, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp fukut@pop.med.hokudai.ac.jp yoshihiro.kawaoka@wisc.edu KeiSato@g.ecc.u-tokyo.ac.jp
Kei Sato
8Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
12Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp fukut@pop.med.hokudai.ac.jp yoshihiro.kawaoka@wisc.edu KeiSato@g.ecc.u-tokyo.ac.jp
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Abstract

During the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and currently, four variants of concerns (VOCs) are considered as the hazardous SARS-CoV-2 variants to the human society1. The newly emerging VOC, the B.1.617.2/Delta variant, closely associates with a huge COVID-19 surge in India in Spring 20212. However, its virological property remains unclear. Here, we show that the B.1.617.2/Delta variant is highly fusogenic, and notably, more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates the spike protein cleavage and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity than the parental virus. Our data suggest that the P681R mutation is a hallmark that characterizes the virological phenotype of the B.1.617.2/Delta variant and is closely associated with enhanced pathogenicity.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of interest: The authors declare that no competing interests exist.

  • We additionally performed animal experiments using the Delta virus as well as the P681R-bearing virus.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 19, 2021.
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SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances viral fusogenicity and pathogenicity
Akatsuki Saito, Takashi Irie, Rigel Suzuki, Tadashi Maemura, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, Jumpei Ito, Jiaqi Wu, Kiyoko Iwatsuki-Horimoto, Mutsumi Ito, Seiya Yamayoshi, Seiya Ozono, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Kumiko Yoshimatsu, Ryoko Kawabata, Takemasa Sakaguchi, Kenzo Tokunaga, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kazuhisa Yoshimura, Akifumi Takaori-Kondo, Masaki Imai, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, Takasuke Fukuhara, Yoshihiro Kawaoka, Kei Sato
bioRxiv 2021.06.17.448820; doi: https://doi.org/10.1101/2021.06.17.448820
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SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances viral fusogenicity and pathogenicity
Akatsuki Saito, Takashi Irie, Rigel Suzuki, Tadashi Maemura, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, Jumpei Ito, Jiaqi Wu, Kiyoko Iwatsuki-Horimoto, Mutsumi Ito, Seiya Yamayoshi, Seiya Ozono, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Kumiko Yoshimatsu, Ryoko Kawabata, Takemasa Sakaguchi, Kenzo Tokunaga, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kazuhisa Yoshimura, Akifumi Takaori-Kondo, Masaki Imai, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, Takasuke Fukuhara, Yoshihiro Kawaoka, Kei Sato
bioRxiv 2021.06.17.448820; doi: https://doi.org/10.1101/2021.06.17.448820

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