Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies
The entry of SARS-CoV-2 into host cells is mediated by the interaction between the spike receptor-binding domain (RBD) and host angiotensin-converting enzyme 2 (ACE2). Certain human antibodies, which target the spike N-terminal domain (NTD) at a distant epitope from the host cell binding surface, ha...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/12/2421 |
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| author | Tina Lusiany Tohru Terada Jun-ichi Kishikawa Mika Hirose David Virya Chen Fuminori Sugihara Hendra Saputra Ismanto Floris J. van Eerden Songling Li Takayuki Kato Hisashi Arase Matsuura Yoshiharu Masato Okada Daron M. Standley |
| author_facet | Tina Lusiany Tohru Terada Jun-ichi Kishikawa Mika Hirose David Virya Chen Fuminori Sugihara Hendra Saputra Ismanto Floris J. van Eerden Songling Li Takayuki Kato Hisashi Arase Matsuura Yoshiharu Masato Okada Daron M. Standley |
| author_sort | Tina Lusiany |
| collection | DOAJ |
| description | The entry of SARS-CoV-2 into host cells is mediated by the interaction between the spike receptor-binding domain (RBD) and host angiotensin-converting enzyme 2 (ACE2). Certain human antibodies, which target the spike N-terminal domain (NTD) at a distant epitope from the host cell binding surface, have been found to augment ACE2 binding and enhance SARS-CoV-2 infection. Notably, these antibodies exert their effect independently of the antibody fragment crystallizable (Fc) region, distinguishing their mode of action from previously described antibody-dependent infection-enhancing (ADE) mechanisms. Building upon previous hypotheses and experimental evidence, we propose that these NTD-targeting infection-enhancing antibodies (NIEAs) achieve their effect through the crosslinking of neighboring spike proteins. In this study, we present refined structural models of NIEA fragment antigen-binding region (Fab)–NTD complexes, supported by molecular dynamics simulations and hydrogen–deuterium exchange mass spectrometry (HDX-MS). Furthermore, we provide direct evidence confirming the crosslinking of spike NTDs by NIEAs. Collectively, our findings advance our understanding of the molecular mechanisms underlying NIEAs and their impact on SARS-CoV-2 infection. |
| first_indexed | 2024-03-08T20:17:24Z |
| format | Article |
| id | doaj.art-a2bc4d0f90d141fcb503218b93aede7c |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-08T20:17:24Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-a2bc4d0f90d141fcb503218b93aede7c2023-12-22T14:49:24ZengMDPI AGViruses1999-49152023-12-011512242110.3390/v15122421Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting AntibodiesTina Lusiany0Tohru Terada1Jun-ichi Kishikawa2Mika Hirose3David Virya Chen4Fuminori Sugihara5Hendra Saputra Ismanto6Floris J. van Eerden7Songling Li8Takayuki Kato9Hisashi Arase10Matsuura Yoshiharu11Masato Okada12Daron M. Standley13Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Tokyo 113-8657, JapanCryo-EM Structural Biology, Institute for Protein Research, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanCryo-EM Structural Biology, Institute for Protein Research, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanDepartment of System Immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanCore Facility, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Osaka 565-0871, JapanDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanDepartment of System Immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanCryo-EM Structural Biology, Institute for Protein Research, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanDepartment of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanCenter for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, JapanCenter for Advanced Modalities and DDS, Osaka University, 2-8 Yamadaoka, Suita 565-0871, JapanDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, JapanThe entry of SARS-CoV-2 into host cells is mediated by the interaction between the spike receptor-binding domain (RBD) and host angiotensin-converting enzyme 2 (ACE2). Certain human antibodies, which target the spike N-terminal domain (NTD) at a distant epitope from the host cell binding surface, have been found to augment ACE2 binding and enhance SARS-CoV-2 infection. Notably, these antibodies exert their effect independently of the antibody fragment crystallizable (Fc) region, distinguishing their mode of action from previously described antibody-dependent infection-enhancing (ADE) mechanisms. Building upon previous hypotheses and experimental evidence, we propose that these NTD-targeting infection-enhancing antibodies (NIEAs) achieve their effect through the crosslinking of neighboring spike proteins. In this study, we present refined structural models of NIEA fragment antigen-binding region (Fab)–NTD complexes, supported by molecular dynamics simulations and hydrogen–deuterium exchange mass spectrometry (HDX-MS). Furthermore, we provide direct evidence confirming the crosslinking of spike NTDs by NIEAs. Collectively, our findings advance our understanding of the molecular mechanisms underlying NIEAs and their impact on SARS-CoV-2 infection.https://www.mdpi.com/1999-4915/15/12/2421infection enhancing antibodycross-linkingSARS-CoV-2spike proteinmolecular dynamicscryo-EM |
| spellingShingle | Tina Lusiany Tohru Terada Jun-ichi Kishikawa Mika Hirose David Virya Chen Fuminori Sugihara Hendra Saputra Ismanto Floris J. van Eerden Songling Li Takayuki Kato Hisashi Arase Matsuura Yoshiharu Masato Okada Daron M. Standley Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies Viruses infection enhancing antibody cross-linking SARS-CoV-2 spike protein molecular dynamics cryo-EM |
| title | Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies |
| title_full | Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies |
| title_fullStr | Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies |
| title_full_unstemmed | Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies |
| title_short | Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies |
| title_sort | enhancement of sars cov 2 infection via crosslinking of adjacent spike proteins by n terminal domain targeting antibodies |
| topic | infection enhancing antibody cross-linking SARS-CoV-2 spike protein molecular dynamics cryo-EM |
| url | https://www.mdpi.com/1999-4915/15/12/2421 |
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