An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape
BackgroundAlthough immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited.MethodsWe retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid poly...
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Frontiers Media S.A.
2025-01-01
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| author | Weiqi Deng Weiqi Deng Xuefeng Niu Ping He Ping He Qihong Yan Qihong Yan Huan Liang Yongping Wang Yongping Wang Lishan Ning Lishan Ning Zihan Lin Zihan Lin Yudi Zhang Xinwei Zhao Xinwei Zhao Liqiang Feng Linbing Qu Ling Chen Ling Chen |
| author_facet | Weiqi Deng Weiqi Deng Xuefeng Niu Ping He Ping He Qihong Yan Qihong Yan Huan Liang Yongping Wang Yongping Wang Lishan Ning Lishan Ning Zihan Lin Zihan Lin Yudi Zhang Xinwei Zhao Xinwei Zhao Liqiang Feng Linbing Qu Ling Chen Ling Chen |
| author_sort | Weiqi Deng |
| collection | DOAJ |
| description | BackgroundAlthough immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited.MethodsWe retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid polymorphism present within germline sequences of IGHV genes. We aassembled the sequences of IgM and IgD repertoire from 130 people to investigate the genetic variations in the population. A dataset comprising 10,643 SARS-CoV-2 spike-specific antibodies, obtained from COV-AbDab, was compiled to assess the impact of SARS-CoV-2 infection on allelic gene utilization. Binding affinity and neutralizing activity were determined using bio-layer interferometry and pseudovirus neutralization assays. Primary docking was performed using ZDOCK (3.0.2) to generate the initial conformation of the antigen-antibody complex, followed by simulations of the complete conformations using Rosetta SnugDock software. The original and simulated structural conformations were visualized and presented using ChimeraX (v1.5).ResultsWe present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of in the population. Our comprehensive analysis of SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies. We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. We found that antibodies carrying the IGHV1-69*02 allele tended to bind to the RBD E2.2 epitope. The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-5*02 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD.DiscussionThis study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics. These findings underscore the importance of Ig alleles in vaccine design and therapeutic antibody development. |
| format | Article |
| id | doaj-art-aabf116dbf064e89bc8bd8b93745327d |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-aabf116dbf064e89bc8bd8b93745327d2025-08-20T02:26:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14713961471396An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escapeWeiqi Deng0Weiqi Deng1Xuefeng Niu2Ping He3Ping He4Qihong Yan5Qihong Yan6Huan Liang7Yongping Wang8Yongping Wang9Lishan Ning10Lishan Ning11Zihan Lin12Zihan Lin13Yudi Zhang14Xinwei Zhao15Xinwei Zhao16Liqiang Feng17Linbing Qu18Ling Chen19Ling Chen20State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaUniversity of Chinese Academy of Science, Beijing, ChinaState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaGuangzhou National Laboratory, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaUniversity of Chinese Academy of Science, Beijing, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaUniversity of Chinese Academy of Science, Beijing, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaUniversity of Chinese Academy of Science, Beijing, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaGuangzhou National Laboratory, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaState Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaGuangzhou National Laboratory, Guangzhou, ChinaBackgroundAlthough immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited.MethodsWe retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid polymorphism present within germline sequences of IGHV genes. We aassembled the sequences of IgM and IgD repertoire from 130 people to investigate the genetic variations in the population. A dataset comprising 10,643 SARS-CoV-2 spike-specific antibodies, obtained from COV-AbDab, was compiled to assess the impact of SARS-CoV-2 infection on allelic gene utilization. Binding affinity and neutralizing activity were determined using bio-layer interferometry and pseudovirus neutralization assays. Primary docking was performed using ZDOCK (3.0.2) to generate the initial conformation of the antigen-antibody complex, followed by simulations of the complete conformations using Rosetta SnugDock software. The original and simulated structural conformations were visualized and presented using ChimeraX (v1.5).ResultsWe present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of in the population. Our comprehensive analysis of SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies. We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. We found that antibodies carrying the IGHV1-69*02 allele tended to bind to the RBD E2.2 epitope. The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-5*02 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD.DiscussionThis study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics. These findings underscore the importance of Ig alleles in vaccine design and therapeutic antibody development.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1471396/fullalleleaffinityantibodyepitopesimmunoglobulin heavy chain (Igh)neutralization |
| spellingShingle | Weiqi Deng Weiqi Deng Xuefeng Niu Ping He Ping He Qihong Yan Qihong Yan Huan Liang Yongping Wang Yongping Wang Lishan Ning Lishan Ning Zihan Lin Zihan Lin Yudi Zhang Xinwei Zhao Xinwei Zhao Liqiang Feng Linbing Qu Ling Chen Ling Chen An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape Frontiers in Immunology allele affinity antibody epitopes immunoglobulin heavy chain (Igh) neutralization |
| title | An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape |
| title_full | An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape |
| title_fullStr | An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape |
| title_full_unstemmed | An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape |
| title_short | An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape |
| title_sort | allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to sars cov 2 mutation escape |
| topic | allele affinity antibody epitopes immunoglobulin heavy chain (Igh) neutralization |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1471396/full |
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