In SARS-CoV-2 delta variants, Spike-P681R and D950N promote membrane fusion, Spike-P681R enhances spike cleavage, but neither substitution affects pathogenicity in hamstersResearch in context
Yuri Furusawa,
Maki Kiso,
Shun Iida,
Ryuta Uraki,
Yuichiro Hirata,
Masaki Imai,
Tadaki Suzuki,
Seiya Yamayoshi,
Yoshihiro Kawaoka
Affiliations
Yuri Furusawa
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
Maki Kiso
Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Shun Iida
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Ryuta Uraki
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
Yuichiro Hirata
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Masaki Imai
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; International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Tadaki Suzuki
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Seiya Yamayoshi
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; International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Corresponding author.
Yoshihiro Kawaoka
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; Pandemic Preparedness, Infection, and Advanced Research Center, The University of Tokyo, Tokyo, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, Madison, WI, USA; Corresponding author.
Summary: Background: The SARS-CoV-2 delta (B.1.617.2 lineage) variant was first identified at the end of 2020 and possessed two unique amino acid substitutions in its spike protein: S-P681R, at the S1/S2 cleavage site, and S-D950N, in the HR1 of the S2 subunit. However, the roles of these substitutions in virus phenotypes have not been fully characterized. Methods: We used reverse genetics to generate Wuhan-D614G viruses with these substitutions and delta viruses lacking these substitutions and explored how these changes affected their viral characteristics in vitro and in vivo. Findings: S-P681R enhanced spike cleavage and membrane fusion, whereas S-D950N slightly promoted membrane fusion. Although S-681R reduced the virus replicative ability especially in VeroE6 cells, neither substitution affected virus replication in Calu-3 cells and hamsters. The pathogenicity of all recombinant viruses tested in hamsters was slightly but not significantly affected. Interpretation: Our observations suggest that the S-P681R and S-D950N substitutions alone do not increase virus pathogenicity, despite of their enhancement of spike cleavage or fusogenicity. Funding: A full list of funding bodies that contributed to this study can be found under Acknowledgments.
