State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian 361102, People's Republic of China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian 361102, People's Republic of China.
Cell Host Microbe. 2022 Sep 14;30(9):1279-1294.e6. doi: 10.1016/j.chom.2022.08.001. Epub 2022 Aug 23.
Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. We characterize the binding and therapeutic efficacies of three CVB1-specific neutralizing antibodies (nAbs) identified for their ability to inhibit host receptor engagement. High-resolution cryo-EM structures showed that these antibodies recognize different epitopes but with an overlapping region in the capsid VP2 protein and specifically the highly variable EF loop. Moreover, they perturb capsid-receptor interactions by binding various viral particle forms. Antibody combinations achieve synergetic neutralization via a stepwise capsid transition and virion disruption, indicating dynamic changes in the virion in response to multiple nAbs targeting the receptor-binding site. Furthermore, this three-antibody cocktail protects against lethal challenge in neonatal mice and limits pancreatitis and viral replication in a non-obese diabetic mouse model. These results illustrate the utility of nAbs for rational design of therapeutics against picornaviruses such as CVB.
柯萨奇病毒 B1（CVB1）是一种新兴的病原体，与包括无菌性脑膜炎、心肌炎和胰腺炎在内的严重新生儿疾病以及 1 型糖尿病的发展有关。我们对三种 CVB1 特异性中和抗体（nAb）的结合和治疗功效进行了表征，这些抗体因其抑制宿主受体结合的能力而被鉴定出来。高分辨率冷冻电镜结构显示，这些抗体识别不同的表位，但在衣壳 VP2 蛋白中有一个重叠区域，特别是高度可变的 EF 环。此外，它们通过结合各种病毒颗粒形式来破坏衣壳-受体相互作用。抗体组合通过逐步衣壳转变和病毒颗粒破坏实现协同中和，表明病毒颗粒在应对针对受体结合位点的多种 nAb 时会发生动态变化。此外，这种三抗体鸡尾酒可预防新生小鼠的致命性攻击，并限制非肥胖型糖尿病小鼠模型中的胰腺炎和病毒复制。这些结果说明了 nAb 在针对柯萨奇病毒等小核糖核酸病毒的合理治疗设计中的应用。
