| Reference | ||
|---|---|---|
| Reference Type | Literature | IEDB_Reference:1045566 |
| Title | A single residue switch mediates the broad neutralization of Rotaviruses. | |
| Authors | 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 | |
| Affiliations | State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, PR China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, PR China; Collaborative Innovation Center for Translation Medical Testing and Application Technology, Department of Medical Technology, Zhangzhou Health Vocational College, Zhangzhou, PR China; Novel Product R&D Department, Xiamen Innovax Biotech Co., Ltd., Xiamen, PR China; State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, PR China. yuhai@xmu.edu.cn; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, PR China. yuhai@xmu.edu.cn; State Key Laboratory o... | |
| Journal | Nat Commun | |
| Year | 2025 | |
| 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. | |
| Curation Last Updated | 2025-03-13 20:02:20 | |
| Epitope | ||
|---|---|---|
| Epitope ID | 2134407 | IEDB_epitope:2134407 |
| Chemical Type | Discontinuous peptide on multi chain | |
| Chain 1 Name | Outer capsid protein VP4 | |
| Source Organism | Human rotavirus G1P[8] | |
| Molecule Name | VP4 | |
| Chain 2 Name | Outer capsid protein VP4 | |
| Source Organism | Human rotavirus G1P[8] | |
| Discontinuous Residues | 1: Y327, G329, G330, L332, T334, D335, F336, L388, P389, V390, G391, A392, W393, V395, L439, R440, T441, R442; U: P68, Q70, N85, N87, T88, N89, E109, H111, N135, R162, Y205, I226 | |
| Epitope Reference Details | ||
|---|---|---|
| Epitope Structure Defines | Partial Epitope | |
| Epitope Name | Epitope of mAb 41# on Rotavirus VP5*/VP8* | |
| Comments | The epitope was described in cited reference [PMID: 35924923]. Additional epitope residues for the mAb (P77, N78, N98, S99, N194) were identified on the adjacent VP8* chain of the upright spike dimer. | |
| Location of Data in Reference | Cited reference | |
| Immunization | ||
|---|---|---|
| Host Organism | Homo sapiens (human) | |
| Host Details | ||
|---|---|---|
| Host Geolocation | contiguous United States of America [ID: GAZ_00003937] | |
| 1st In Vivo Process | ||
|---|---|---|
| In Vivo Process Type | Exposure with existing immune reactivity without evidence for disease | |
| Disease State | healthy | |
| 1st Immunogen | ||
|---|---|---|
| Epitope Relation | Taxonomic Parent | |
| Object Type | Organism | |
| Organism | Human rotavirus A (Human group A rotavirus) | |
| Immunization Comments | ||
|---|---|---|
| Immunization Comments | Generation of the mAb was described in cited reference [PMID: 28637924]. Rotavirus specific IgA+ antibody secreting cells were isolated from proximal jejunum resections of patients undergoing bariatric surgery. Paired immunoglobulin variable heavy and light chain genes were cloned for expression as IgG molecules. | |
| B Cell Assay | ||
|---|---|---|
| Qualitative Measurement | Positive | |
| Method/Technique | immuno staining | |
| Measurement of | qualitative binding | |
| Assayed Antibody | ||
|---|---|---|
| Assayed Antibody Source Material | Purified Immunoglobulin | |
| Assayed Antibody Immunoglobulin Domain | Entire Antibody | |
| Assayed Antibody Purification Status | Monoclonal | |
| Assayed Antibody Name | mAb 41# | |
| Assayed Antibody Heavy Chain Type | IgG | |
| Assayed Antibody Light Chain Type | Lambda | |
| Antigen | ||
|---|---|---|
| Epitope Relation | Taxonomic Sibling | |
| Object Type | Organism | |
| Organism | Rotavirus A Hu/Wa-20-MA/USA/1974/G1P[8] | |
| Antigen Details | ||
|---|---|---|
| Antigen Reference Name | Wa G1P[8] | |
| Assay Reference Details | ||
|---|---|---|
| Assay Comments by IEDB Curator | The epitope specific mAb bound MA-104 cells infected by human, bovine, canine, sheep, mouse, swine, and simian rotavirus strains as demonstrated by immunofluorescence. | |
| Location of Assay Data in Reference | Supplementary Figure 4 | |