手足口病肠道病毒跨血清型广谱中和抗体的表位结构与作用机制研究

手足口病（HFMD）是我国当前重要的公共卫生问题，病原体主要包括EV71、CA16、CA6和CA10等不同血清型的肠道病毒。跨血清型的广谱中和抗体及表位对于研究HFMD广谱疫苗和治疗药物具有重要意义。课题组在前期工作中发现了对不同血清型肠道病毒EV71、CA16、CA6和CA10具有广谱中和能力的单克隆抗体，在体内、外感染模型中兼具良好的交叉保护效果，但尚不了解该类抗体的表位结构特征和作用机制。本研究将在前期工作基础上，应用低温电镜（Cryo-EM）三维重构与抗体诱导逃逸突变等技术，获得该类单抗与病毒颗粒复合物的Cryo-EM结构，解析广谱中和表位的表位结构特征与关键氨基酸位点，并应用病毒学和生化分析方法研究抗体与肠道病毒的相互作用，揭示该类中和抗体的抗病毒作用机制，为发展新型HFMD广谱疫苗和抗病毒治疗药物提供理论基础和科学依据。

Hand, foot, and mouth disease (HFMD) is an important public health concern in China mainland caused by a variety of enterovirus of different serotypes, which includes EV71, CA16, CA6, CA10 and other HEVs. It would be of significance to study the cross-serotype neutralizing antibodies and their epitopes in developing broad-spectrum vaccines and therapeutic drugs for HFMD. In our previous study, a class of broad-spectrum neutralizing antibodies against different serotypes of EV71, CA16, CA6 and CA10 had been discovered and also shown to have good cross-protection in vivo and in vitro. However, the epitope characteristics and mechanism of protection still remain unknown. In this study, we intend to identify the critical amino acid residues and structural characteristics of the broad-spectrum neutralizing epitope by using three-dimensional reconstruction of cryo-electron microscopy (Cryo-EM) and antibody-induced escape mutation methods. In addition, to demonstrate the antiviral mechanism, series of virological and biochemical analysis will be performed. The anticipated results will provide the theoretical basis and scientific evidence for further studying the broad-spectrum HFMD vaccine and antiviral drugs.