A single residue switch mediates the broad neutralization of Rotaviruses

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...

Full description

Saved in:
Bibliographic Details
Main 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
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56114-3
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-1723

Similar Items