Abstract
Sporadic outbreaks caused by coxsackievirus A4 (CV-A4) have been reported worldwide. To further elucidate the detailed genetic characteristics and evolutionary recombination events of CV-A4, virus samples from nationwide hand, foot and mouth disease (HFMD) surveillance, encompassing 27 out of the 31 provinces in China, were investigated. Comprehensive and systematic phylogenetic analyses were performed by using 29 complete genomes, 142 complete CV-A4 VP1 sequences. Four genotypes (A, B, C and D) and five sub-genotypes (C1-C5) were re-identified based on the complete VP1 sequences. C2 is the predominant sub-genotype of CV-A4 associated with HFMD and has evolved into 3 clusters. Cluster 1 is a major cluster that has been persistently and extensively circulating in China since 2006 and has been associated with all severe cases. All the sequences showed high homology with the CV-A4 prototype in the P1 region, while higher identities with CV-A5, CV-14 and CV-16 in the P2 and P3 regions. Recombination analysis revealed that C2 had two specific genetic recombination patterns with other EV-A prototypes in the 5′-UTR and 3D region compared with C5. These recombination patterns might be associated with the increased transmissibility of C2 viruses, which were obtained due to their persistent and extensive circulation in populations.
Highlights
Hand, foot and mouth disease (HFMD), which is caused by multiple types of enteroviruses (EV), is a common childhood viral infection that is typically mild and self-limiting and often affects children under five years of age[1,2,3]
According to the dendrogram based on the 5′-untranslated region (UTR) region, we found that the C2 and C5 sequences were clustered with the CV-A6 prototype, while the C4 sequences were located in the same clade with the prototypes of Coxsackievirus A4 (CV-A4), CV-A14 and coxsackievirus A16 (CV-A16)
As a member of enterovirus A (EV-A), CV-A4 has circulated in the world for many years since the prototype strain High Point was isolated in 194823
Summary
Foot and mouth disease (HFMD), which is caused by multiple types of enteroviruses (EV), is a common childhood viral infection that is typically mild and self-limiting and often affects children under five years of age[1,2,3]. Several epidemics caused by CV-A4 in many regions indicate that CV-A4 is an important pathogen and co-circulates with other EVs15,16. Two HFMD outbreaks occurred in Taiwan in 2004 and 2006, both of www.nature.com/scientificreports/. After these outbreaks, CV-A4 raised concerns again when it began to co-circulate with CV-A16 in 2010. P2 and P3 are precursors of the non-structural proteins 2A–2C and 3A–3D, respectively. We performed a nationwide analysis using 142 complete VP1 sequences of CV-A4 samples from 1996 and 2017, together with 13 complete genome sequences determined in this study to provide a comprehensive molecular characterization and recombination analysis of CV-A4
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