Discovery, recognized antigenic structures, and evolution of cross-serotype broadly neutralizing antibodies from porcine B-cell repertoires against foot-and-mouth disease virus

Fengjuan Li; Shanquan Wu; Lv Lv; Shulun Huang; Zelin Zhang; Zhaxi Zerang; Pinghua Li; Yimei Cao; Huifang Bao; Pu Sun; Xingwen Bai; Yong He; Yuanfang Fu; Hong Yuan; Xueqing Ma; Zhixun Zhao; Jing Zhang; Jian Wang; Tao Wang; Dong Li; Qiang Zhang; Jijun He; Zaixin Liu; Zengjun Lu; Dongsheng Lei; Kun Li

doi:10.1371/journal.ppat.1012623

Discovery, recognized antigenic structures, and evolution of cross-serotype broadly neutralizing antibodies from porcine B-cell repertoires against foot-and-mouth disease virus

PLoS Pathog. 2024 Oct 15;20(10):e1012623. doi: 10.1371/journal.ppat.1012623. eCollection 2024 Oct.

Authors

Fengjuan Li^{1

2}, Shanquan Wu³, Lv Lv^{1

2}, Shulun Huang^{1

2}, Zelin Zhang³, Zhaxi Zerang³, Pinghua Li^{1

2}, Yimei Cao^{1

2}, Huifang Bao^{1

2}, Pu Sun^{1

2}, Xingwen Bai^{1

2}, Yong He⁴, Yuanfang Fu^{1

2}, Hong Yuan^{1

2}, Xueqing Ma^{1

2}, Zhixun Zhao^{1

2}, Jing Zhang^{1

2}, Jian Wang^{1

2}, Tao Wang^{1

2}, Dong Li^{1

2}, Qiang Zhang^{1

2}, Jijun He^{1

2}, Zaixin Liu^{1

2}, Zengjun Lu^{1

2}, Dongsheng Lei^{1

3}, Kun Li^{1

2}

Affiliations

¹ State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, P. R. China.
² Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, P. R. China.
³ School of Physical Science and Technology, Electron Microscopy Centre of Lanzhou University, Lanzhou University, Lanzhou, P. R. China.
⁴ School of Pharmaceutical Sciences, Shandong University, Ji'nan, P. R. China.

Abstract

It is a great challenge to isolate the broadly neutralizing antibodies (bnAbs) against foot-and-mouth disease virus (FMDV) due to its existence as seven distinct serotypes without cross-protection. Here, by vaccination of pig with FMDV serotypes O and A whole virus antigens, we obtained 10 bnAbs against serotypes O, A and/or Asia1 by dissecting 216 common clonotypes of two serotypes O and A specific porcine B-cell receptor (BCR) gene repertoires containing total 12720 B cell clones, indicating the induction of cross-serotype bnAbs after sequential vaccination with serotypes O and A antigens. The majority of porcine bnAbs (9/10) were derived from terminally differentiated B cells of different clonal lineages, which convergently targeted the conserved "RGDL" motif on structural protein VP1 of FMDV by mimicking receptor recognition to inhibit viral attachment to cells. Cryo-EM complex structures revealed that the other bnAb pOA-2 specifically targets a novel inter-pentamer antigen structure surrounding the viral three-fold axis, with a highly conserved determinant at residue 68 on VP2. This unique binding pattern enabled cross-serotype neutralization by destabilizing the viral particle. The evolutionary analysis of pOA-2 demonstrated its origin from an intermediate B-cell, emphasizing the crucial role of somatic hypermutations (SHMs) in balancing the breadth and potency of neutralization. However, excessive SHMs may deviate from the trajectory of broad neutralization. This study provides a strategy to uncover bnAbs against highly mutable pathogens and the cross-serotype antigenic structures to explore broadly protective FMDV vaccine.

Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Animals
Antibodies, Neutralizing* / immunology
Antibodies, Viral* / immunology
Antigens, Viral / genetics
Antigens, Viral / immunology
B-Lymphocytes* / immunology
Broadly Neutralizing Antibodies / immunology
Foot-and-Mouth Disease Virus* / immunology
Foot-and-Mouth Disease* / immunology
Foot-and-Mouth Disease* / prevention & control
Foot-and-Mouth Disease* / virology
Serogroup
Swine
Swine Diseases / immunology
Swine Diseases / virology

Substances

Antibodies, Viral
Antibodies, Neutralizing
Antigens, Viral
Broadly Neutralizing Antibodies

Grants and funding

This work was supported by grants from the National Key R&D Program of China (2021YFD1800304 to Z.L.), the National Natural Science Foundation of China (Nos. 32373028 to K.L., 32171300 to D.L., 32072873 to Y.C., and 32302884 to H.Y), Fundamental Research Funds for the Central Universities (lzujbky-2021-ct05 to D.L). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.