Structures of Foot-and-Mouth Disease Virus with Bovine Neutralizing Antibodies Reveal the Determinant of Intraserotype Cross-Neutralization

文献类型： 外文期刊

第一作者： He, Yong

作者： He, Yong;Yang, Cheng;He, Yong;Li, Kun;Wang, Li;Cao, Yimei;Li, Pinghua;Sun, Pu;Bao, Huifang;Zhou, Shasha;Wang, Sheng;Bai, Xingwen;Liu, Zaixin;Lu, Zengjun;He, Yong;Lou, Zhiyong;Sun, Zixian;Liu, Xuerong;Zhao, Lixia;Fan, Xiuli

作者机构：

关键词： foot-and-mouth disease virus; bovine antibody; cross-reaction; interpentamer epitope

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：6.549； 五年影响因子：5.78 ）

ISSN： 0022-538X

年卷期： 2021 年 95 卷 24 期

页码：

收录情况： SCI

摘要： Foot-and-mouth disease virus (FMDV) exhibits broad antigenic diversity with poor intraserotype cross-neutralizing activity. Studies of the determinant involved in this diversity are essential for the development of broadly protective vaccines. In this work, we isolated a bovine antibody, designated R55, that displays cross-reaction with both FMDV A/AF/72 (hereafter named FMDV-AAF) and FMDV A/WH/09 (hereafter named FMDV-AWH) but only has a neutralizing effect on FMDV-AWH. Near-atomic resolution structures of FMDV-AAF-R55 and FMDV-AWH-R55 show that R55 engages the capsids of both FMDV-AAF and FMDV-AWH near the icosahedral 3-fold axis and binds to the beta B and BC/HI-loops of VP2 and to the B-B knob of VP3. The common interaction residues are highly conserved, which is the major determinant for cross-reaction with both FMDV-AAF and FMDV-AWH. In addition, the cryo-EM structure of the FMDV-AWH-R55 complex also shows that R55 binds to VP3E70 located at the VP3 BC-loop in an adjacent pentamer, which enhances the acid and thermal stabilities of the viral capsid. This may prevent capsid dissociation and genome release into host cells, eventually leading to neutralization of the viral infection. In contrast, R55 binds only to the FMDV-AAF capsid within one pentamer due to the (VP3)E70G variation, which neither enhances capsid stability nor neutralizes FMDV-AAF infection. The (VP3)E70G mutation is the major determinant involved in the neutralizing differences between FMDV-AWH and FMDV-AAF. The crucial amino acid (VP3)E70 is a key component of the neutralizing epitopes, which may aid in the development of broadly protective vaccines. IMPORTANCE Foot-and-mouth disease virus (FMDV) causes a highly contagious and economically devastating disease in cloven-hoofed animals, and neutralizing antibodies play critical roles in the defense against viral infections. Here, we isolated a bovine antibody (R55) using the single B cell antibody isolation technique. Enzyme-linked immunosorbent assays (ELISA) and virus neutralization tests (VNT) showed that R55 displays cross-reactions with both FMDV-AWH and FMDV-AAF but only has a neutralizing effect on FMDV-AWH. Cryo-EM structures, fluorescence-based thermal stability assays and acid stability assays showed that R55 engages the capsid of FMDV-AWH near the icosahedral 3-fold axis and informs an interpentamer epitope, which overstabilizes virions to hinder capsid dissociation to release the genome, eventually leading to neutralization of viral infection. The crucial amino acid (VP3)E70 forms a key component of neutralizing epitopes, and the determination of the (VP3)E70G mutation involved in the neutralizing differences between FMDV-AWH and FMDV-AAF could aid in the development of broadly protective vaccines.

分类号：

  • 相关文献
作者其他论文 更多>>

微信小程序