Xu Yi, Ma Shuzhi, Zhu Limeng, Huang Zhiqiu, Chen Liyun, Xu Yuhua, Yin Haibin, Peng Tao, Wang Yi
Guangzhou Women and Children's Medical Center, Guangzhou Medical University Guangzhou, China.
Guangdong South China United Vaccine Institute, Guangzhou, China; Sino-French Hoffmann Institute of Immunology, State Key Laboratory of Respiratory Disease, College of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
Antiviral Res. 2017 Jan;137:67-75. doi: 10.1016/j.antiviral.2016.11.008. Epub 2016 Nov 15.
The Enterovirus A71 (EV-A71) subgenogroup C4 is prevalent in China. EV-A71 causes hand, foot and mouth disease (HFMD) in children and may lead to severe neurological diseases. The development of antiviral and protective vaccines against EV-A71 is significantly hindered by the lack of suitable animal models to recapitulate human neurological symptoms. In this study, GZ-CII, a highly virulent EV-A71 subgenogroup C4 strain, was isolated from hospitalized children with HFMD. Intraperitoneal infections of GZ-CII resulted in progressive neurological disease in mice as old as 14 days. Administration of an inactivated EV-A71 vaccine or an anti-EV-A71 immune serum protected the mice against the GZ-CII infection. This demonstrated that a mouse model with EV-A71 GZ-CII could be used to evaluate potential vaccine candidates and therapeutics for subgenogroup C4. Comparing the genome sequence of GZ-CII with that of the avirulent EV-A71 subgenogroup C4 strain revealed unique mutations in GZ-CII. When mutation VP2-K149I was introduced into the nonpathogenic EV-A71 subgenogroup C4 strain, the variant similar to GZ-CII significantly increased viral replication and virulence in mice. These results indicated that the VP2-K149I mutation played an important role in enhancing the virulence of the EV-A71 subgenogroup C4 strain in mice, and that mice infected with the GZ-CII strain are a promising model for evaluating vaccines and therapeutics against the EV-A71 subgenogroup C4.
肠道病毒A71型（EV - A71）C4亚基因组在中国流行。EV - A71可导致儿童手足口病（HFMD），并可能引发严重的神经疾病。由于缺乏合适的动物模型来重现人类神经症状，针对EV - A71的抗病毒和保护性疫苗的研发受到了显著阻碍。在本研究中，从患手足口病的住院儿童中分离出了高毒力的EV - A71 C4亚基因组毒株GZ - CII。对14日龄小鼠进行腹腔注射GZ - CII可导致进行性神经疾病。接种灭活的EV - A71疫苗或抗EV - A71免疫血清可保护小鼠免受GZ - CII感染。这表明携带EV - A71 GZ - CII的小鼠模型可用于评估C4亚基因组潜在的候选疫苗和治疗方法。将GZ - CII的基因组序列与无毒力的EV - A71 C4亚基因组毒株的序列进行比较，发现GZ - CII存在独特的突变。当将突变VP2 - K149I引入无毒力的EV - A71 C4亚基因组毒株时，类似于GZ - CII的变体显著增加了病毒在小鼠体内的复制和毒力。这些结果表明，VP2 - K149I突变在增强EV - A71 C4亚基因组毒株在小鼠体内的毒力方面发挥了重要作用，并且感染GZ - CII毒株的小鼠是评估针对EV - A71 C4亚基因组的疫苗和治疗方法的有前景的模型。
