A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context
Summary: Background: Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicr...
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Elsevier
2024-12-01
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| author | Yuhan Li Xianwen Zhang Wanbo Tai Xinyu Zhuang Huicheng Shi Shumin Liao Xinyang Yu Rui Mei Xingzhao Chen Yanhong Huang Yubin Liu Jianying Liu Yang Liu Yibin Zhu Penghua Wang Mingyao Tian Guocan Yu Liang Li Gong Cheng |
| author_facet | Yuhan Li Xianwen Zhang Wanbo Tai Xinyu Zhuang Huicheng Shi Shumin Liao Xinyang Yu Rui Mei Xingzhao Chen Yanhong Huang Yubin Liu Jianying Liu Yang Liu Yibin Zhu Penghua Wang Mingyao Tian Guocan Yu Liang Li Gong Cheng |
| author_sort | Yuhan Li |
| collection | DOAJ |
| description | Summary: Background: Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic. Methods: Through systematic bioinformatics analysis of 496,606 sequences of Omicron variants, we obtained 40 amino acid substitutions that occurred with high frequency in the S protein. Utilising pseudoviruses and a trans-complementation system of SARS-CoV-2, we identified the effect of high-frequency mutations on viral infectivity and elucidated the molecular mechanisms. Finally, we evaluated the impact of a key emerging mutation on the immune protection induced by the SARS-CoV-2 VLP mRNA vaccine in a murine model. Findings: We identified a proline-to-leucine substitution at the 1263rd residue of the Spike protein, and upon investigating the relative frequencies across multiple Omicron sublineages, we found a trend of increasing frequency for P1263L. The substitution significantly enhances the capacity for S-mediated viral entry and improves the immunogenicity of a virus-like particle mRNA vaccine. Mechanistic studies showed that this mutation is located in the FERM binding motif of the cytoplasmic tail and impairs the interaction between the S protein and the Ezrin/Radixin/Moesin proteins. Additionally, this mutation facilitates the incorporation of S proteins into SARS-CoV-2 virions. Interpretation: This study offers mechanistic insight into the constantly increasing transmissibility of SARS-CoV-2 Omicron variants and provides a meaningful optimisation strategy for vaccine development against SARS-CoV-2. Funding: This study was supported by grants from the National Key Research and Development Plan of China (2021YFC2302405, 2022YFC2303200, 2021YFC2300200 and 2022YFC2303400), the National Natural Science Foundation of China (32188101, 32200772, 82422049, 82241082, 32270182, 82372254, 82271872, 82341046, 32100755 and 82102389), Shenzhen Medical Research Fund (B2404002, A2303036), the Shenzhen Bay Laboratory Startup Fund (21330111), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010). The New Cornerstone Science Foundation through the New Cornerstone Investigator Program, and the Xplorer Prize from Tencent Foundation. |
| format | Article |
| id | doaj-art-30828ee07f364a019c79b0ea962e961b |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| spelling | doaj-art-30828ee07f364a019c79b0ea962e961b2024-11-13T04:29:59ZengElsevierEBioMedicine2352-39642024-12-01110105437A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in contextYuhan Li0Xianwen Zhang1Wanbo Tai2Xinyu Zhuang3Huicheng Shi4Shumin Liao5Xinyang Yu6Rui Mei7Xingzhao Chen8Yanhong Huang9Yubin Liu10Jianying Liu11Yang Liu12Yibin Zhu13Penghua Wang14Mingyao Tian15Guocan Yu16Liang Li17Gong Cheng18New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, China; Corresponding authors.Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, ChinaChangchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, State Key Laboratory of Pathogen and Biosecurity, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, ChinaNew Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaDepartment of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, ChinaKey Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, ChinaInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, ChinaInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, ChinaDepartment of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, ChinaNew Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, ChinaInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, ChinaNew Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaDepartment of Immunology, School of Medicine, The University of Connecticut Health Center, Farmington, CT, 06030, USAChangchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, State Key Laboratory of Pathogen and Biosecurity, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, China; Corresponding authors.Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China; Corresponding authors.Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Corresponding author.New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen 518000, China; Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China; Southwest United Graduate School, Kunming 650092, China; Corresponding author. New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.Summary: Background: Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic. Methods: Through systematic bioinformatics analysis of 496,606 sequences of Omicron variants, we obtained 40 amino acid substitutions that occurred with high frequency in the S protein. Utilising pseudoviruses and a trans-complementation system of SARS-CoV-2, we identified the effect of high-frequency mutations on viral infectivity and elucidated the molecular mechanisms. Finally, we evaluated the impact of a key emerging mutation on the immune protection induced by the SARS-CoV-2 VLP mRNA vaccine in a murine model. Findings: We identified a proline-to-leucine substitution at the 1263rd residue of the Spike protein, and upon investigating the relative frequencies across multiple Omicron sublineages, we found a trend of increasing frequency for P1263L. The substitution significantly enhances the capacity for S-mediated viral entry and improves the immunogenicity of a virus-like particle mRNA vaccine. Mechanistic studies showed that this mutation is located in the FERM binding motif of the cytoplasmic tail and impairs the interaction between the S protein and the Ezrin/Radixin/Moesin proteins. Additionally, this mutation facilitates the incorporation of S proteins into SARS-CoV-2 virions. Interpretation: This study offers mechanistic insight into the constantly increasing transmissibility of SARS-CoV-2 Omicron variants and provides a meaningful optimisation strategy for vaccine development against SARS-CoV-2. Funding: This study was supported by grants from the National Key Research and Development Plan of China (2021YFC2302405, 2022YFC2303200, 2021YFC2300200 and 2022YFC2303400), the National Natural Science Foundation of China (32188101, 32200772, 82422049, 82241082, 32270182, 82372254, 82271872, 82341046, 32100755 and 82102389), Shenzhen Medical Research Fund (B2404002, A2303036), the Shenzhen Bay Laboratory Startup Fund (21330111), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010). The New Cornerstone Science Foundation through the New Cornerstone Investigator Program, and the Xplorer Prize from Tencent Foundation.http://www.sciencedirect.com/science/article/pii/S2352396424004730SARS-CoV-2High-frequency mutationsSpike variantsVirus entryVirus-like particle mRNA vaccine |
| spellingShingle | Yuhan Li Xianwen Zhang Wanbo Tai Xinyu Zhuang Huicheng Shi Shumin Liao Xinyang Yu Rui Mei Xingzhao Chen Yanhong Huang Yubin Liu Jianying Liu Yang Liu Yibin Zhu Penghua Wang Mingyao Tian Guocan Yu Liang Li Gong Cheng A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context EBioMedicine SARS-CoV-2 High-frequency mutations Spike variants Virus entry Virus-like particle mRNA vaccine |
| title | A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context |
| title_full | A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context |
| title_fullStr | A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context |
| title_full_unstemmed | A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context |
| title_short | A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicityResearch in context |
| title_sort | substitution at the cytoplasmic tail of the spike protein enhances sars cov 2 infectivity and immunogenicityresearch in context |
| topic | SARS-CoV-2 High-frequency mutations Spike variants Virus entry Virus-like particle mRNA vaccine |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424004730 |
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