Structures of Foot-and-mouth Disease Virus with neutralizing antibodies derived from recovered natural host reveal a mechanism for cross-serotype neutralization.

Yong He,Zaixin Liu,Sheng Wang,Guoqiang Zhu,Xingwen Bai,Huifang Bao,Pinghua Li,Cheng Yang,Yimei Cao,Zihe Rao,Pu Sun,Kun Li,Zengjun Lu,Xuerong Liu,Zixian Sun,Zhiyong Lou,Richard J Kuhn

doi:10.1371/journal.ppat.1009507

Abstract

The development of a universal vaccine against foot-and-mouth disease virus (FMDV) is hindered by cross-serotype antigenic diversity and by a lack of knowledge regarding neutralization of the virus in natural hosts. In this study, we isolated serotype O-specific neutralizing antibodies (NAbs) (F145 and B77) from recovered natural bovine hosts by using the single B cell antibody isolation technique. We also identified a serotype O/A cross-reacting NAb (R50) and determined virus-NAb complex structures by cryo-electron microscopy at near-atomic resolution. F145 and B77 were shown to engage the capsid of FMDV-O near the icosahedral threefold axis, binding to the BC/HI-loop of VP2. In contrast, R50 engages the capsids of both FMDV-O and FMDV-A between the 2- and 5-fold axes and binds to the BC/EF/GH-loop of VP1 and to the GH-loop of VP3 from two adjacent protomers, revealing a previously unknown antigenic site. The cross-serotype neutralizing epitope recognized by R50 is highly conserved among serotype O/A. These findings help to elucidate FMDV neutralization by natural hosts and provide epitope information for the development of a universal vaccine for cross-serotype protection against FMDV.

Highlights

Foot-and-mouth disease virus (FMDV), a small nonenveloped single-stranded positive-sense RNA virus, is the causative agent of footand-mouth disease (FMD)
FMDV is the causative agent of foot-and-mouth disease, one of the most contagious and economically devastating diseases of cloven-hoofed animals
Structures of FMDV with neutralizing antibodies reveal a mechanism for cross-serotype neutralization the structures were deposited into the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) with the following accession numbers: FMDV-OTi-B77, EMD-30558, PDB 7D3K; FMDVOTi-F145, EMD-30559, PDB 7D3L; FMDV-OTiR50, EMD-30560, PDB 7D3M; and FMDV-AWHR50, EMD-30565, PDB 7D3R

Summary

Introduction

Foot-and-mouth disease virus (FMDV), a small nonenveloped single-stranded positive-sense RNA virus (genus Aphthovirus within the family Picornaviridae), is the causative agent of footand-mouth disease (FMD). FMD is one of the most contagious and economically devastating diseases of cloven-hoofed animals in many developing regions of Asia, Africa and South America[1,2,3]. FMDV exists as seven immunologically distinct serotypes (O, A, C, SAT1, SAT2, SAT3 and Asia1)[4]. Serotypes O and A are the most common causative agents of FMDV outbreaks globally[5,6]. Vaccination is believed to play a predominant role in the control and prevention of FMDV[7]. The antigenic diversities of the currently known epitopes throughout FMDV serotypes and the lack of understanding of FMDV neutralization in natural hosts limit the development of a vaccine that is able to provide cross-serotype protection[8,9,10,11]

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