Song Yang, Zhang Yong, Han Zhenzhi, Xu Wen, Xiao Jinbo, Wang Xianjun, Wang Jianxing, Yang Jianfang, Yu Qiuli, Yu Deshan, Chen Jianhua, Huang Wei, Li Jie, Xie Tong, Lu Huanhuan, Ji Tianjiao, Yang Qian, Yan Dongmei, Zhu Shuangli, Xu Wenbo
WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 155, Changbai Road, Changping District, Beijing, 102206, China.
Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei Province, China.
Virus Evol. 2020 Jul 8;6(2):veaa048. doi: 10.1093/ve/veaa048. eCollection 2020 Jul.
Hand, foot, and mouth disease (HFMD) is a common global epidemic. From 2008 onwards, many HFMD outbreaks caused by coxsackievirus A6 (CV-A6) have been reported worldwide. Since 2013, with a dramatically increasing number of CV-A6-related HFMD cases, CV-A6 has become the predominant HFMD pathogen in mainland China. Phylogenetic analysis based on the capsid gene revealed that subtype D3 dominated the CV-A6 outbreaks. Here, we performed a large-scale (near) full-length genetic analysis of global and Chinese CV-A6 variants, including 158 newly sequenced samples collected extensively in mainland China between 2010 and 2018. During the global transmission of subtype D3 of CV-A6, the noncapsid gene continued recombining, giving rise to a series of viable recombinant hybrids designated evolutionary lineages, and each lineage displayed internal consistency in both genetic and epidemiological features. The emergence of lineage -A since 2005 has triggered CV-A6 outbreaks worldwide, with a rate of evolution estimated at 4.17 × 10 substitutions site year based on a large number of monophyletic open reading frame sequences, and created a series of lineages chronologically through varied noncapsid recombination events. In mainland China, lineage -A has generated another two novel widespread lineages (-J and -L) through recombination within the enterovirus A gene pool, with robust estimates of occurrence time. Lineage -A, -J, and -L infections presented dissimilar clinical manifestations, indicating that the conservation of the CV-A6 capsid gene resulted in high transmissibility, but the lineage-specific noncapsid gene might influence pathogenicity. Potentially important amino acid substitutions were further predicted among CV-A6 variants. The evolutionary phenomenon of noncapsid polymorphism within the same subtype observed in CV-A6 was uncommon in other leading HFMD pathogens; such frequent recombination happened in fast-spreading CV-A6, indicating that the recovery of deleterious genomes may still be ongoing within CV-A6 quasispecies. CV-A6-related HFMD outbreaks have caused a significant public health burden and pose a great threat to children's health; therefore, further surveillance is greatly needed to understand the full genetic diversity of CV-A6 in mainland China.
手足口病（HFMD）是一种常见的全球流行性疾病。自2008年起，全球多地报告了由柯萨奇病毒A6（CV-A6）引起的手足口病疫情。自2013年以来，随着CV-A6相关手足口病病例数量急剧增加，CV-A6已成为中国大陆手足口病的主要病原体。基于衣壳基因的系统发育分析表明，D3亚型主导了CV-A6疫情。在此，我们对全球及中国的CV-A6变异株进行了大规模（近乎）全长基因分析，其中包括2010年至2018年间在中国大陆广泛收集的158个新测序样本。在CV-A6 D3亚型的全球传播过程中，非衣壳基因持续重组，产生了一系列具有生存能力的重组杂交体，即进化谱系，每个谱系在遗传和流行病学特征上都表现出内部一致性。自2005年以来，A谱系的出现引发了全球范围内的CV-A6疫情，基于大量单系开放阅读框序列估计其进化速率为4.17×10⁻⁴替换/位点/年，并通过不同的非衣壳重组事件按时间顺序产生了一系列谱系。在中国大陆，A谱系通过肠道病毒A基因库内的重组又产生了另外两个广泛传播的新谱系（-J和-L），并对其出现时间进行了可靠估计。A、J和L谱系感染呈现出不同的临床表现，这表明CV-A6衣壳基因的保守性导致了高传播性，但谱系特异性的非衣壳基因可能影响致病性。我们还进一步预测了CV-A6变异株中潜在重要的氨基酸替换。在CV-A6中观察到的同一亚型内非衣壳多态性的进化现象在其他主要手足口病病原体中并不常见；这种频繁的重组发生在快速传播的CV-A6中，表明有害基因组在CV-A6准种内可能仍在不断恢复。CV-A6相关的手足口病疫情已造成重大公共卫生负担，对儿童健康构成巨大威胁；因此，迫切需要进一步监测以了解中国大陆CV-A6的完整遗传多样性。
