Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin, China.
Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, Jilin, China.
J Virol. 2018 May 14;92(11). doi: 10.1128/JVI.00303-18. Print 2018 Jun 1.
Coxsackievirus A6 (CV-A6) is an emerging pathogen associated with hand, foot, and mouth disease (HFMD). Its genetic characterization and pathogenic properties are largely unknown. Here, we report 39 circulating CV-A6 strains isolated in 2013 from HFMD patients in northeast China. Three major clusters of CV-A6 were identified and related to CV-A6, mostly from Shanghai, indicating that domestic CV-A6 strains were responsible for HFMD emerging in northeast China. Four full-length CV-A6 genomes representing each cluster were sequenced and analyzed further. Bootscanning tests indicated that all four CV-A6-Changchun strains were most likely recombinants between the CV-A6 prototype Gdula and prototype CV-A4 or CV-A4-related viruses, while the recombination pattern was related to, yet distinct from, the strains isolated from other regions of China. Furthermore, different CV-A6 strains showed different capabilities of viral replication, release, and pathogenesis in a mouse model. Further analyses indicated that viral protein 2C contributed to the diverse pathogenic abilities of CV-A6 by causing autophagy and inducing cell death. To our knowledge, this study is the first to report lethal and nonlethal strains of CV-A6 associated with HFMD. The 2C protein region may play a key role in the pathogenicity of CV-A6 strains. Hand, foot, and mouth disease (HFMD) is a major and persistent threat to infants and children. Besides the most common pathogens, such as enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), other enteroviruses are increasingly contributing to HFMD. The present study focused on the recently emerged CV-A6 strain. We found that CV-A6 strains isolated in Changchun City in northeast China were associated with domestic origins. These Changchun viruses were novel recombinants of the CV-A6 prototype Gdula and CV-A4. Our results imply that measures to control CV-A6 transmission are urgently needed. Further analyses revealed differing pathogenicities in strains isolated in a neonatal mouse model. One of the possible causes has been narrowed down to the viral protein 2C, using phylogenetic studies, viral sequences, and direct tests on cultured human cells. Thus, the viral 2C protein is a promising target for antiviral drugs to prevent CV-A6-induced tissue damage.
柯萨奇病毒 A6（CV-A6）是一种与手足口病（HFMD）相关的新兴病原体。其遗传特征和致病特性在很大程度上尚不清楚。在这里，我们报告了 2013 年在中国东北地区从 HFMD 患者中分离出的 39 株循环 CV-A6 株。鉴定出三个主要的 CV-A6 簇，与 CV-A6 密切相关，主要来自上海，表明国内 CV-A6 株是导致中国东北地区 HFMD 流行的原因。对代表每个簇的四个全长 CV-A6 基因组进行了测序和进一步分析。Bootscanning 测试表明，所有四个长春 CV-A6 株均最有可能是 CV-A6 原型 Gdula 与原型 CV-A4 或 CV-A4 相关病毒之间的重组体，而重组模式与从中国其他地区分离的菌株相关，但又有所不同。此外，不同的 CV-A6 株在小鼠模型中表现出不同的病毒复制、释放和发病能力。进一步分析表明，病毒蛋白 2C 通过引起自噬和诱导细胞死亡，导致 CV-A6 的不同致病能力。据我们所知，这是首次报道与 HFMD 相关的致命和非致命的 CV-A6 株。2C 蛋白区域可能在 CV-A6 株的致病性中起关键作用。手足口病（HFMD）是婴儿和儿童的主要且持续的威胁。除了常见的病原体，如肠道病毒 A71（EV-A71）和柯萨奇病毒 A16（CV-A16）之外，其他肠道病毒也越来越多地导致 HFMD。本研究集中在最近出现的 CV-A6 株上。我们发现，中国东北长春市分离的 CV-A6 株与国内起源有关。这些长春病毒是 CV-A6 原型 Gdula 和 CV-A4 的新型重组体。我们的研究结果表明，迫切需要采取措施控制 CV-A6 的传播。进一步的分析表明，在新生小鼠模型中分离的株具有不同的致病性。使用系统发育研究、病毒序列和对培养的人细胞的直接测试，已将一个可能的原因缩小到病毒蛋白 2C。因此，病毒 2C 蛋白是预防 CV-A6 诱导的组织损伤的有希望的抗病毒药物靶标。
