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Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.
Nature. 2022 02; 602(7896):300-306.Nat

Abstract

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society1. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2). However, the virological properties of B.1.617.2/Delta remain 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 cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.

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Authors+Show Affiliations

Saito A
Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan. Center for Animal Disease Control, University of Miyazaki, Miyazaki, Japan. Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan.
Irie T
Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Suzuki R
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
Maemura T
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Nasser H
Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan. Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
Uriu K
Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kosugi Y
Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Shirakawa K
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sadamasu K
Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
Kimura I
Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Ito J
Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Wu J
Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan. CREST, Japan Science and Technology Agency, Saitama, Japan.
Iwatsuki-Horimoto K
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Ito M
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Yamayoshi S
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
Loeber S
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.
Tsuda M
Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan. Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Hokkaido, Japan.
Wang L
Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan. Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Hokkaido, Japan.
Ozono S
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Butlertanaka EP
Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
Tanaka YL
Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
Shimizu R
Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan. Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Shimizu K
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
Yoshimatsu K
Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan.
Kawabata R
Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Sakaguchi T
Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Tokunaga K
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Yoshida I
Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
Asakura H
Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
Nagashima M
Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
Kazuma Y
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nomura R
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Horisawa Y
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yoshimura K
Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
Takaori-Kondo A
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Imai M
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
Genotype to Phenotype Japan (G2P-Japan) Consortium
No affiliation info available
Tanaka S
Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan. tanaka@med.hokudai.ac.jp. Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Hokkaido, Japan. tanaka@med.hokudai.ac.jp.
Nakagawa S
Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan. so@tokai.ac.jp. CREST, Japan Science and Technology Agency, Saitama, Japan. so@tokai.ac.jp.
Ikeda T
Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan. ikedat@kumamoto-u.ac.jp.
Fukuhara T
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan. fukut@pop.med.hokudai.ac.jp.
Kawaoka Y
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu. Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. yoshihiro.kawaoka@wisc.edu. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu.
Sato K
Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. KeiSato@g.ecc.u-tokyo.ac.jp. CREST, Japan Science and Technology Agency, Saitama, Japan. KeiSato@g.ecc.u-tokyo.ac.jp.

MeSH

Amino Acid SubstitutionAnimalsAntibodies, NeutralizingAntibodies, ViralCOVID-19CricetinaeGiant CellsMaleMembrane FusionMesocricetusMutationPhylogenySARS-CoV-2Spike Glycoprotein, CoronavirusVirulenceVirus Replication

Pub Type(s)

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

Language

eng

PubMed ID

34823256

Citation

Saito, Akatsuki, et al. "Enhanced Fusogenicity and Pathogenicity of SARS-CoV-2 Delta P681R Mutation." Nature, vol. 602, no. 7896, 2022, pp. 300-306.
Saito A, Irie T, Suzuki R, et al. Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. Nature. 2022;602(7896):300-306.
Saito, A., Irie, T., Suzuki, R., Maemura, T., Nasser, H., Uriu, K., Kosugi, Y., Shirakawa, K., Sadamasu, K., Kimura, I., Ito, J., Wu, J., Iwatsuki-Horimoto, K., Ito, M., Yamayoshi, S., Loeber, S., Tsuda, M., Wang, L., Ozono, S., ... Sato, K. (2022). Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. Nature, 602(7896), 300-306. https://doi.org/10.1038/s41586-021-04266-9
Saito A, et al. Enhanced Fusogenicity and Pathogenicity of SARS-CoV-2 Delta P681R Mutation. Nature. 2022;602(7896):300-306. PubMed PMID: 34823256.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. AU - Saito,Akatsuki, AU - Irie,Takashi, AU - Suzuki,Rigel, AU - Maemura,Tadashi, AU - Nasser,Hesham, AU - Uriu,Keiya, AU - Kosugi,Yusuke, AU - Shirakawa,Kotaro, AU - Sadamasu,Kenji, AU - Kimura,Izumi, AU - Ito,Jumpei, AU - Wu,Jiaqi, AU - Iwatsuki-Horimoto,Kiyoko, AU - Ito,Mutsumi, AU - Yamayoshi,Seiya, AU - Loeber,Samantha, AU - Tsuda,Masumi, AU - Wang,Lei, AU - Ozono,Seiya, AU - Butlertanaka,Erika P, AU - Tanaka,Yuri L, AU - Shimizu,Ryo, AU - Shimizu,Kenta, AU - Yoshimatsu,Kumiko, AU - Kawabata,Ryoko, AU - Sakaguchi,Takemasa, AU - Tokunaga,Kenzo, AU - Yoshida,Isao, AU - Asakura,Hiroyuki, AU - Nagashima,Mami, AU - Kazuma,Yasuhiro, AU - Nomura,Ryosuke, AU - Horisawa,Yoshihito, AU - Yoshimura,Kazuhisa, AU - Takaori-Kondo,Akifumi, AU - Imai,Masaki, AU - ,, AU - Tanaka,Shinya, AU - Nakagawa,So, AU - Ikeda,Terumasa, AU - Fukuhara,Takasuke, AU - Kawaoka,Yoshihiro, AU - Sato,Kei, Y1 - 2021/11/25/ PY - 2021/07/22/received PY - 2021/11/18/accepted PY - 2021/11/26/pubmed PY - 2022/2/24/medline PY - 2021/11/25/entrez SP - 300 EP - 306 JF - Nature JO - Nature VL - 602 IS - 7896 N2 - During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society1. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2). However, the virological properties of B.1.617.2/Delta remain 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 cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/34823256/Enhanced_fusogenicity_and_pathogenicity_of_SARS_CoV_2_Delta_P681R_mutation_ DB - PRIME DP - Unbound Medicine ER -