我国大陆柯萨奇病毒A4的C2亚型重组株进化分析

Evolutionary signature of recombinant sub-genotype C2 of coxsackievirus A4 in Chinese mainland

目的了解我国大陆手足口病(hand,foot and mouth disease,HFMD)主要病原基因组的型间重组情况,分析柯萨奇病毒A组(coxsackievirus A,CVA)4型主要重组株的进化起源。方法收集Genbank中收录的2000—2012(含)年之间CVA2/4/5/6/8/10^(-3)/12/14/16型和肠道病毒A组71型(enterovirus 71,EV-A71)全基因组序列,应用RDP4和Simplot软件扫描重组事件;对CVA4的主要重组株,基于P3区基因开展进一步分析,应用BEAST.v1.10^(-3).4软件构建系统进化树,并进行系统地理发生分析。结果本研究关注的手足口病主要病原中,CVA2/4/6/8/14/16和EV-A71均筛选到重组株,这提示重组在肠道病毒A组中普遍存在,重组位点多位于5′-UTR、P2和P3区。CVA4主要重组株与EV-A71(JF799986)在P2区发生重组,发生重组的P3基因平均碱基替代速率(mean rate)为7.095×10^(-3)位点/年(95%HPD区间:5.458×10^(-3)~8.885×10^(-3)位点/年),最早共同祖先(the most recent common ancestor,tMRCA)可以追溯到1997.87年(95%HPD区间:1985.71—2005.23年)。结论我国大陆地区肠道病毒A组流行株均存在型间重组的现象,CVA4的C2亚型重组株可能为近年来我国大陆CVA4持续流行并引发手足口病的主要原因。本研究阐明CVA4重组株的起源进化及分子流行特征,为CVA4毒株监控和手足口病等相疾病防控工作的开展提供依据。

Objective To investigate the inter-genotype recombination of major pathogens causing hand,foot,and mouth disease(HFMD)in Chinese mainland and to analyze the evolutionary origin of coxsackievirus A4(CVA4)recombinant strains.Methods The complete gene sequences of CVA2/4/5/6/8/10^(-3)/12/14/16 and enterovirus 71(EV-A71)were acquired from Genebank during 2000 and 2012,and the recombination events were scanned by RDP4 and Simplot software.The main recombinant strains of CVA4 were further analyzed based on P3 region.The phylogenetic tree was constructed using BEAST.v1.10^(-3).4 software and geographic relations were analyzed.Results Among the major pathogens of HFMD in the study,recombinant events were identified in all CVA2/4/6/8/14/16 and EV-A71 strains,suggesting that recombination was prevalent in EV-A group viruses,and the recombination sites were mostly located at 5′-UTR,P2 and P3 regions.The main recombinant strains of CVA4 shared P2 region with EV-A71(JF799986),and the mean rate of the P3 region in recombinant strains was 7.095×10^(-3)-3 site/year(95%HPD interval:5.458×10^(-3)-3—8.885×10^(-3)-3 site/year),and the most recent common ancestor(tMRCA)could be traced back to the year of 1997.87(95%HPD interval:1985.71—2005.23).Conclusions Inter-genotype recombination events are common in EV-A groups in Chinese mainland,and the CVA4C2sub-genotype recombinant strain may be the major pathogen of CVA4-related HFMD circulating in Chinese mainland during the past few years.This study clarifies the origin,evolution,molecular and epidemiological characteristics of CVA4recombinant strains,and provides a basis for the surveillance of CVA4and the prevention and control of HFMD.