State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou (P.R. China).
College of Pharmaceutical Sciences, Shandong University, Jinan, China.
PLoS Pathog. 2023 Nov 20;19(11):e1011811. doi: 10.1371/journal.ppat.1011811. eCollection 2023 Nov.
Foot-and-mouth disease virus (FMDV) serotype A is antigenically most variable within serotypes. The structures of conserved and variable antigenic sites were not well resolved. Here, a historical A/AF72 strain from A22 lineage and a latest A/GDMM/2013 strain from G2 genotype of Sea97 lineage were respectively used as bait antigen to screen single B cell antibodies from bovine sequentially vaccinated with A/WH/CHA/09 (G1 genotype of Sea97 lineage), A/GDMM/2013 and A/AF72 antigens. Total of 39 strain-specific and 5 broad neutralizing antibodies (bnAbs) were isolated and characterized. Two conserved antigenic sites were revealed by the Cryo-EM structures of FMDV serotype A with two bnAbs W2 and W125. The contact sites with both VH and VL of W125 were closely around icosahedral threefold axis and covered the B-C, E-F, and H-I loops on VP2 and the B-B knob and H-I loop on VP3; while contact sites with only VH of W2 concentrated on B-B knob, B-C and E-F loops on VP3 scattering around the three-fold axis of viral particle. Additional highly conserved epitopes also involved key residues of VP158, VP1147 and both VP272 / VP1147 as determined respectively by bnAb W153, W145 and W151-resistant mutants. Furthermore, the epitopes recognized by 20 strain-specific neutralization antibodies involved the key residues located on VP3 68 for A/AF72 (11/20) and VP3 175 position for A/GDMM/2013 (9/19), respectively, which revealed antigenic variation between different strains of serotype A. Analysis of antibody-driven variations on capsid of two virus strains showed a relatively stable VP2 and more variable VP3 and VP1. This study provided important information on conserve and variable antigen structures to design broad-spectrum molecular vaccine against FMDV serotype A.
口蹄疫病毒（FMDV）血清型 A 在血清型内具有最强的抗原变异性。保守和可变抗原位点的结构尚未得到很好的解决。在这里，分别使用 A22 谱系的历史 A/AF72 株和 G2 基因型 Sea97 谱系的最新 A/GDMM/2013 株作为诱饵抗原，从先后用 A/WH/CHA/09（Sea97 谱系的 G1 基因型）、A/GDMM/2013 和 A/AF72 抗原免疫的牛中筛选单 B 细胞抗体。共分离和鉴定了 39 株特异性和 5 株广谱中和抗体（bnAb）。通过 FMDV 血清型 A 的 Cryo-EM 结构揭示了两个保守的抗原位点，其中两个 bnAb 为 W2 和 W125。W125 与 VH 和 VL 的接触位点紧密围绕着二十面体的三重轴，并覆盖了 VP2 的 B-C、E-F 和 H-I 环以及 VP3 的 B-B 旋钮和 H-I 环；而仅与 VH 接触的 W2 接触位点集中在 VP3 的 B-B 旋钮、B-C 和 E-F 环上，分散在病毒粒子的三重轴周围。额外的高度保守表位还涉及 VP158、VP1147 和 VP272/VP1147 的关键残基，这分别由 bnAb W153、W145 和 W151 抗性突变体确定。此外，20 株特异性中和抗体识别的表位涉及位于 VP3 68 位置的 A/AF72（11/20）和 VP3 175 位置的 A/GDMM/2013（9/19）的关键残基，这揭示了血清型 A 不同毒株之间的抗原变异。对两种病毒株衣壳的抗体驱动变异分析表明，VP2 相对稳定，而 VP3 和 VP1 则更具变异性。本研究为设计针对 FMDV 血清型 A 的广谱分子疫苗提供了关于保守和可变抗原结构的重要信息。
