A Single Mutation in the VP1 Gene of Enterovirus 71 Enhances Viral Binding to Heparan Sulfate and Impairs Viral Pathogenicity in Mice
A Single Mutation in the VP1 Gene of Enterovirus 71 Enhances Viral Binding to Heparan Sulfate and Impairs Viral Pathogenicity in Mice
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肠道病毒 71 型 VP1 基因的单一突变增强病毒与硫酸乙酰肝素的结合并削弱病毒对小鼠的致病性
DOI：
10.3390/v12080883
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发表时间：
2020-08-01
期刊：
影响因子：
4.7
通讯作者：
Zheng, Zhenhua
中科院分区：
文献类型：
--
作者：
Ke, Xianliang;Zhang, Yuan;Zheng, Zhenhua
肠道病毒71型(EV71)是人类手足口病(HHFMD)的主要病原体，并已进化为利用各种细胞受体进行感染。然而，受体偏好与EV71毒力之间的关系尚未完全揭示。利用反向遗传学方法，我们发现VP1中的一个E98K突变是导致病毒在体外快速复制的原因。E98K突变以硫酸乙酰肝素(HS)依赖的方式增强EV71-GZCII与细胞的结合，并减弱EV71-GZCII对BALB/c小鼠的毒力，表明HS结合特性与病毒毒力呈负相关。HS在小鼠不同组织的血管内皮细胞中广泛表达，并与清道夫受体B2(SCARB2)弱共定位。CGZCII-98K病毒与小鼠组织匀浆的结合效率较高，小鼠组织和血液中的cGZCII-98K病毒滴度明显低于cGZCII病毒滴度。总之，这些发现表明，cGZCII-98K病毒的增强吸附可能通过HS发生，不能支持EV71在体内的有效复制。我们的研究证实了HS结合位点在EV71感染中的作用，并强调了HS受体在EV71致病中的重要性。
Enterovirus 71 (EV71) is the major causative pathogen of human hand, foot, and mouth disease (hHFMD) and has evolved to use various cellular receptors for infection. However, the relationship between receptor preference and EV71 virulence has not been fully revealed. By using reverse genetics, we identified that a single E98K mutation in VP1 is responsible for rapid viral replication in vitro. The E98K mutation enhanced binding of EV71-GZCII to cells in a heparan sulfate (HS)-dependent manner, and it attenuated the virulence of EV71-GZCII in BALB/c mice, indicating that the HS-binding property is negatively associated with viral virulence. HS is widely expressed in vascular endothelial cells in different mouse tissues, and weak colocalization of HS with scavenger receptor B2 (SCARB2) was detected. The cGZCII-98K virus bound more efficiently to mouse tissue homogenates, and the cGZCII-98K virus titers in mouse tissues and blood were much lower than the cGZCII virus titers. Together, these findings suggest that the enhanced adsorption of the cGZCII-98K virus, which likely occurs through HS, is unable to support the efficient replication of EV71 in vivo. Our study confirmed the role of HS-binding sites in EV71 infection and highlighted the importance of the HS receptor in EV71 pathogenesis.