Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity

Yang Song; Yong Zhang; Zhenzhi Han; Wen Xu; Jinbo Xiao; Xianjun Wang; Jianxing Wang; Jianfang Yang; Qiuli Yu; Deshan Yu; Jianhua Chen; Wei Huang; Jie Li; Tong Xie; Huanhuan Lu; Tianjiao Ji; Qian Yang; Dongmei Yan; Shuangli Zhu; Wenbo Xu

doi:10.1093/ve/veaa048

Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity

Virus Evol. 2020 Jul 8;6(2):veaa048. doi: 10.1093/ve/veaa048. eCollection 2020 Jul.

Authors

Yang Song¹, Yong Zhang^{1

2}, Zhenzhi Han¹, Wen Xu³, Jinbo Xiao¹, Xianjun Wang⁴, Jianxing Wang⁴, Jianfang Yang⁵, Qiuli Yu⁶, Deshan Yu⁷, Jianhua Chen⁷, Wei Huang⁸, Jie Li⁹, Tong Xie¹⁰, Huanhuan Lu¹, Tianjiao Ji¹, Qian Yang¹, Dongmei Yan¹, Shuangli Zhu¹, Wenbo Xu^{1

2

11}

Affiliations

¹ 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.
² Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei Province, China.
³ Yunnan Center for Disease Control and Prevention, Kunming, Yunnan Province, China.
⁴ Shandong Center for Disease Control and Prevention, Jinan, Shandong Province, China.
⁵ Shanxi Center for Disease Control and Prevention, Taiyuan, Shanxi Province, China.
⁶ Hebei Center for Disease Control and Prevention, Shijiazhuang, Hebei Province, China.
⁷ Gansu Center for Disease Control and Prevention, Lanzhou, Gansu Province, China.
⁸ Chongqing Center for Disease Control and Prevention, Chongqing City, China.
⁹ Beijing Center for Disease Control and Prevention, Beijing City, China.
¹⁰ Tianjin Center for Disease Control and Prevention, Tianjin City, China.
¹¹ Anhui University of Science and Technology, Anhui Province, China.

Abstract

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 VP1 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^-3 substitutions site^- ¹ year^-1 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.

Keywords: Coxsackievirus A6; evolutionary dynamics; foot and mouth disease; genetic recombination; hand; pathogenicity; phylogeny; whole-genome analysis.