Two Cross-Protective Antigen Sites on Foot-and-Mouth Disease Virus Serotype O Structurally Revealed by Broadly Neutralizing Antibodies from Cattle
Two Cross-Protective Antigen Sites on Foot-and-Mouth Disease Virus Serotype O Structurally Revealed by Broadly Neutralizing Antibodies from Cattle
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牛的广泛中和抗体揭示了 O 型口蹄疫病毒的两个交叉保护性抗原位点
DOI：
10.1128/jvi.00881-21
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发表时间：
2021-11-01
影响因子：
5.4
通讯作者：
Lu, Zengjun
中科院分区：
文献类型：
--
作者：
Li, Kun;He, Yong;Lu, Zengjun
口蹄疫是引起口蹄疫的病原，口蹄疫是家畜最具传染性和经济破坏性的疾病之一。O型口蹄疫病毒的抗原结构相当复杂，尤其是那些能引起交叉保护性中和抗体反应的部位。摘要口蹄疫病毒(FMDV)是一种感染偶蹄动物的高度传染性病毒。中和抗体在抗病毒感染中起着关键作用。虽然已经确定了五个可诱导中和抗体的已知抗原位点，但对交叉保护性抗原位点的研究仍然很少。我们用13个牛来源的广中和单抗(BNAbs)定位了两个交叉保护的抗原位点，这些抗体能够中和O型口蹄疫病毒3个拓扑型的4个谱系。其中一个抗原位点是由bNab C4和C4类抗体识别的一组新的VP3抗原表位形成的。FMDV-OTI(O/西藏/99)-C4复合体的冷冻电子显微镜结构显示与VP3和围绕口蹄疫病毒颗粒二十面体三重轴的一个新的原构体间抗原表位密切接触，这远远超出了已知的抗原位点4。决定C4和C4类抗体对衣壳的中和功能的关键决定因素是βB(T65)、B-C环(T68)、E-F环(E131和K134)和H-I环(G196)。另一个抗原位点由9个bNAbs(B57、B73、B77、B82、F28、F145、F150、E46和E54)识别的VP2上的两组表位组成，属于O型口蹄疫病毒的已知抗原位点2。值得注意的是，bNab C4有效地促进了口蹄疫病毒对病毒颗粒的损伤反应释放RNA，提示靶向表位含有颗粒解体的触发机制。本研究揭示了两个能在牛体内产生交叉中和抗体的交叉保护性抗原位点，为设计针对O型口蹄疫病毒的广谱分子疫苗提供了新的结构信息。口蹄疫病毒是口蹄疫的病原体，口蹄疫是家畜最具传染性和经济破坏性的疾病之一。O型口蹄疫病毒的抗原结构相当复杂，尤其是那些能引起交叉保护性中和抗体反应的部位。单抗中和抗体既是抵抗口蹄疫病毒感染的重要防御成分，又是精细分析抗原结构的宝贵工具。在本研究中，我们从天然宿主牛的O型口蹄疫病毒的13个bNAbs中发现了一组新的VP3抗原表位，揭示了VP2和VP3上的两个交叉保护性抗原位点。针对该新表位的抗体C4在感染前有效地促进了病毒颗粒的分解和RNA的释放，这可能表明口蹄疫病毒的一个脆弱区域。本研究揭示了O型口蹄疫病毒交叉保护性抗原位点的新结构信息，为未来口蹄疫广谱疫苗的研究提供了有价值的有力支持。
FMDV is the causative agent of foot-and-mouth disease (FMD), which is one of the most contagious and economically devastating diseases of domestic animals. The antigenic structure of FMDV serotype O is rather complicated, especially for those sites that can elicit a cross-protective neutralizing antibody response. ABSTRACT Foot-and-mouth disease virus (FMDV) is a highly contagious virus that infects cloven-hoofed animals. Neutralizing antibodies play critical roles in antiviral infection. Although five known antigen sites that induce neutralizing antibodies have been defined, studies on cross-protective antigen sites are still scarce. We mapped two cross-protective antigen sites using 13 bovine-derived broadly neutralizing monoclonal antibodies (bnAbs) capable of neutralizing 4 lineages within 3 topotypes of FMDV serotype O. One antigen site was formed by a novel cluster of VP3-focused epitopes recognized by bnAb C4 and C4-like antibodies. The cryo-electron microscopy (cryo-EM) structure of the FMDV-OTi (O/Tibet/99)-C4 complex showed close contact with VP3 and a novel interprotomer antigen epitope around the icosahedral 3-fold axis of the FMDV particle, which is far beyond the known antigen site 4. The key determinants of the neutralizing function of C4 and C4-like antibodies on the capsid were βB (T65), the B-C loop (T68), the E-F loop (E131 and K134), and the H-I loop (G196), revealing a novel antigen site on VP3. The other antigen site comprised two group epitopes on VP2 recognized by 9 bnAbs (B57, B73, B77, B82, F28, F145, F150, E46, and E54), which belong to the known antigen site 2 of FMDV serotype O. Notably, bnAb C4 potently promoted FMDV RNA release in response to damage to viral particles, suggesting that the targeted epitope contains a trigger mechanism for particle disassembly. This study revealed two cross-protective antigen sites that can elicit cross-reactive neutralizing antibodies in cattle and provided new structural information for the design of a broad-spectrum molecular vaccine against FMDV serotype O. IMPORTANCE FMDV is the causative agent of foot-and-mouth disease (FMD), which is one of the most contagious and economically devastating diseases of domestic animals. The antigenic structure of FMDV serotype O is rather complicated, especially for those sites that can elicit a cross-protective neutralizing antibody response. Monoclonal neutralization antibodies provide both crucial defense components against FMDV infection and valuable tools for fine analysis of the antigenic structure. In this study, we found a cluster of novel VP3-focused epitopes using 13 bnAbs against FMDV serotype O from natural host cattle, which revealed two cross-protective antigen sites on VP2 and VP3. Antibody C4 targeting this novel epitope potently promoted viral particle disassembly and RNA release before infection, which may indicate a vulnerable region of FMDV. This study reveals new structural information about cross-protective antigen sites of FMDV serotype O, providing valuable and strong support for future research on broad-spectrum vaccines against FMD.