High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has elicited a worldwide pandemic since late 2019. There has been ~675 million confirmed coronavirus disease 2019 (COVID-19) cases, leading to more than 6.8 million deaths as of March 1, 2023. Five SARS-CoV-2 variants of...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-04-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00534-2 |
| _version_ | 1797846058119725056 |
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| author | Yufeng Luo Shuo Liu Jiguo Xue Ye Yang Junxuan Zhao Ying Sun Bolun Wang Shenyi Yin Juan Li Yuchao Xia Feixiang Ge Jiqiao Dong Lvze Guo Buqing Ye Weijin Huang Youchun Wang Jianzhong Jeff Xi |
| author_facet | Yufeng Luo Shuo Liu Jiguo Xue Ye Yang Junxuan Zhao Ying Sun Bolun Wang Shenyi Yin Juan Li Yuchao Xia Feixiang Ge Jiqiao Dong Lvze Guo Buqing Ye Weijin Huang Youchun Wang Jianzhong Jeff Xi |
| author_sort | Yufeng Luo |
| collection | DOAJ |
| description | Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has elicited a worldwide pandemic since late 2019. There has been ~675 million confirmed coronavirus disease 2019 (COVID-19) cases, leading to more than 6.8 million deaths as of March 1, 2023. Five SARS-CoV-2 variants of concern (VOCs) were tracked as they emerged and were subsequently characterized. However, it is still difficult to predict the next dominant variant due to the rapid evolution of its spike (S) glycoprotein, which affects the binding activity between cellular receptor angiotensin-converting enzyme 2 (ACE2) and blocks the presenting epitope from humoral monoclonal antibody (mAb) recognition. Here, we established a robust mammalian cell-surface-display platform to study the interactions of S-ACE2 and S-mAb on a large scale. A lentivirus library of S variants was generated via in silico chip synthesis followed by site-directed saturation mutagenesis, after which the enriched candidates were acquired through single-cell fluorescence sorting and analyzed by third-generation DNA sequencing technologies. The mutational landscape provides a blueprint for understanding the key residues of the S protein binding affinity to ACE2 and mAb evasion. It was found that S205F, Y453F, Q493A, Q493M, Q498H, Q498Y, N501F, and N501T showed a 3–12-fold increase in infectivity, of which Y453F, Q493A, and Q498Y exhibited at least a 10-fold resistance to mAbs REGN10933, LY-CoV555, and REGN10987, respectively. These methods for mammalian cells may assist in the precise control of SARS-CoV-2 in the future. |
| first_indexed | 2024-04-09T17:48:52Z |
| format | Article |
| id | doaj.art-08b465ad54d5418d8dde96917057d9c9 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-09T17:48:52Z |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-08b465ad54d5418d8dde96917057d9c92023-04-16T11:06:41ZengNature Publishing GroupCell Discovery2056-59682023-04-019111510.1038/s41421-023-00534-2High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2Yufeng Luo0Shuo Liu1Jiguo Xue2Ye Yang3Junxuan Zhao4Ying Sun5Bolun Wang6Shenyi Yin7Juan Li8Yuchao Xia9Feixiang Ge10Jiqiao Dong11Lvze Guo12Buqing Ye13Weijin Huang14Youchun Wang15Jianzhong Jeff Xi16Department of Biomedical Engineering, College of Future Technology, Peking UniversityGraduate School of Chinese Academy of Medical Sciences & Peking Union Medical CollegeInstitute of Health Service and Transfusion MedicineDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityAcademy for Advanced Interdisciplinary Studies, Peking UniversityDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityGeneX Health Co. LtdDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityGeneX Health Co. LtdGeneX Health Co. LtdDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityDivision of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC)Graduate School of Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Biomedical Engineering, College of Future Technology, Peking UniversityAbstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has elicited a worldwide pandemic since late 2019. There has been ~675 million confirmed coronavirus disease 2019 (COVID-19) cases, leading to more than 6.8 million deaths as of March 1, 2023. Five SARS-CoV-2 variants of concern (VOCs) were tracked as they emerged and were subsequently characterized. However, it is still difficult to predict the next dominant variant due to the rapid evolution of its spike (S) glycoprotein, which affects the binding activity between cellular receptor angiotensin-converting enzyme 2 (ACE2) and blocks the presenting epitope from humoral monoclonal antibody (mAb) recognition. Here, we established a robust mammalian cell-surface-display platform to study the interactions of S-ACE2 and S-mAb on a large scale. A lentivirus library of S variants was generated via in silico chip synthesis followed by site-directed saturation mutagenesis, after which the enriched candidates were acquired through single-cell fluorescence sorting and analyzed by third-generation DNA sequencing technologies. The mutational landscape provides a blueprint for understanding the key residues of the S protein binding affinity to ACE2 and mAb evasion. It was found that S205F, Y453F, Q493A, Q493M, Q498H, Q498Y, N501F, and N501T showed a 3–12-fold increase in infectivity, of which Y453F, Q493A, and Q498Y exhibited at least a 10-fold resistance to mAbs REGN10933, LY-CoV555, and REGN10987, respectively. These methods for mammalian cells may assist in the precise control of SARS-CoV-2 in the future.https://doi.org/10.1038/s41421-023-00534-2 |
| spellingShingle | Yufeng Luo Shuo Liu Jiguo Xue Ye Yang Junxuan Zhao Ying Sun Bolun Wang Shenyi Yin Juan Li Yuchao Xia Feixiang Ge Jiqiao Dong Lvze Guo Buqing Ye Weijin Huang Youchun Wang Jianzhong Jeff Xi High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 Cell Discovery |
| title | High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 |
| title_full | High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 |
| title_fullStr | High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 |
| title_full_unstemmed | High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 |
| title_short | High-throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of SARS-CoV-2 |
| title_sort | high throughput screening of spike variants uncovers the key residues that alter the affinity and antigenicity of sars cov 2 |
| url | https://doi.org/10.1038/s41421-023-00534-2 |
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