A single residue switch mediates the broad neutralization of Rotaviruses
Abstract Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56114-3 |
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| author | Yang Huang Feibo Song Yuanjun Zeng Hui Sun Roufang Sheng Xuechun Wang Liqin Liu Guoxing Luo Yanan Jiang Yaling Chen Mengxuan Zhang Shiyin Zhang Ying Gu Hai Yu Shaowei Li Tingdong Li Qingbing Zheng Shengxiang Ge Jun Zhang Ningshao Xia |
| author_facet | Yang Huang Feibo Song Yuanjun Zeng Hui Sun Roufang Sheng Xuechun Wang Liqin Liu Guoxing Luo Yanan Jiang Yaling Chen Mengxuan Zhang Shiyin Zhang Ying Gu Hai Yu Shaowei Li Tingdong Li Qingbing Zheng Shengxiang Ge Jun Zhang Ningshao Xia |
| author_sort | Yang Huang |
| collection | DOAJ |
| description | Abstract Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of bNAbs and their underlying neutralization mechanism. Here, focusing on the pivotal viral protein VP4 of rotavirus (RV), we identify a potent bNAb, 7H13, exhibiting broad-spectrum neutralization across diverse RV genotypes and demonstrating strong prevention of virus infection in female mice. A combination of time-resolved cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) analysis reveals a counterintuitive dynamic process of virus inactivation, in which 7H13 asymmetrically binds to a conserved epitope in the capsid-proximal aspect of VP4, triggers a conformational switch in a critical residue—F418—thereby disrupts the meta-stable conformation of VP4 essential for normal viral infection. Structure-guided mutagenesis corroborates the essential role of the 7H13 heavy chain I54 in activating F418 switch and destabilizing VP4. These findings define an atypical NAbs’ neutralization mechanism and reveal a potential type of virus vulnerable site for universal vaccine and therapeutics design. |
| format | Article |
| id | doaj-art-25dc943f4de64622bee3d45e63a02378 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-25dc943f4de64622bee3d45e63a023782025-01-26T12:40:26ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56114-3A single residue switch mediates the broad neutralization of RotavirusesYang Huang0Feibo Song1Yuanjun Zeng2Hui Sun3Roufang Sheng4Xuechun Wang5Liqin Liu6Guoxing Luo7Yanan Jiang8Yaling Chen9Mengxuan Zhang10Shiyin Zhang11Ying Gu12Hai Yu13Shaowei Li14Tingdong Li15Qingbing Zheng16Shengxiang Ge17Jun Zhang18Ningshao Xia19State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityState Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen UniversityAbstract Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of bNAbs and their underlying neutralization mechanism. Here, focusing on the pivotal viral protein VP4 of rotavirus (RV), we identify a potent bNAb, 7H13, exhibiting broad-spectrum neutralization across diverse RV genotypes and demonstrating strong prevention of virus infection in female mice. A combination of time-resolved cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) analysis reveals a counterintuitive dynamic process of virus inactivation, in which 7H13 asymmetrically binds to a conserved epitope in the capsid-proximal aspect of VP4, triggers a conformational switch in a critical residue—F418—thereby disrupts the meta-stable conformation of VP4 essential for normal viral infection. Structure-guided mutagenesis corroborates the essential role of the 7H13 heavy chain I54 in activating F418 switch and destabilizing VP4. These findings define an atypical NAbs’ neutralization mechanism and reveal a potential type of virus vulnerable site for universal vaccine and therapeutics design.https://doi.org/10.1038/s41467-025-56114-3 |
| spellingShingle | Yang Huang Feibo Song Yuanjun Zeng Hui Sun Roufang Sheng Xuechun Wang Liqin Liu Guoxing Luo Yanan Jiang Yaling Chen Mengxuan Zhang Shiyin Zhang Ying Gu Hai Yu Shaowei Li Tingdong Li Qingbing Zheng Shengxiang Ge Jun Zhang Ningshao Xia A single residue switch mediates the broad neutralization of Rotaviruses Nature Communications |
| title | A single residue switch mediates the broad neutralization of Rotaviruses |
| title_full | A single residue switch mediates the broad neutralization of Rotaviruses |
| title_fullStr | A single residue switch mediates the broad neutralization of Rotaviruses |
| title_full_unstemmed | A single residue switch mediates the broad neutralization of Rotaviruses |
| title_short | A single residue switch mediates the broad neutralization of Rotaviruses |
| title_sort | single residue switch mediates the broad neutralization of rotaviruses |
| url | https://doi.org/10.1038/s41467-025-56114-3 |
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