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As the proportion of non-enterovirus 71 and non-coxsackievirus A16 which proportion of composition in the hand, foot, and mouth pathogenic spectrum gradually increases worldwide, the attention paid to other enteroviruses has increased. As a member of the species enterovirus A, coxsackievirus A14 (CVA14) has been epidemic around the world until now since it has been isolated. However, studies on CVA14 are poor and the effective population size, evolutionary dynamics, and recombination patterns of CVA14 are not well understood. In this study, 15 CVA14 strains were isolated from HFMD patients in mainland China from 2009 to 2019, and the complete sequences of CVA14 in GenBank as research objects were analyzed. CVA14 was divided into seven genotypes A-G based on an average nucleotide difference of the full-length VP1 coding region of more than 15%. Compared with the CVA14 prototype strain, the 15 CVA14 strains showed 84.0–84.7% nucleotide identity in the complete genome and 96.9–97.6% amino acid identity in the encoding region. Phylodynamic analysis based on 15 CVA14 strains and 22 full-length VP1 sequences in GenBank showed a mean substitution rate of 5.35 × 10−3 substitutions/site/year (95% HPD: 4.03–6.89 × 10−3) and the most recent common ancestor (tMRCA) of CVA14 dates back to 1942 (95% HPD: 1930–1950). The Bayesian skyline showed that the effective population size had experienced a decrease–increase–decrease fluctuation since 2004. The phylogeographic analysis indicated two and three possible migration paths in the world and mainland China, respectively. Four recombination patterns with others of species enterovirus A were observed in 15 CVA14 strains, among which coxsackievirus A2 (CVA2), coxsackievirus A4 (CVA4), coxsackievirus A6 (CVA6), coxsackievirus A8 (CVA8), and coxsackievirus A12 (CVA12) may act as recombinant donors in multiple regions. This study has filled the gap in the molecular epidemiological characteristics of CVA14, enriched the global CVA14 sequence database, and laid the epidemiological foundation for the future study of CVA14 worldwide. [ABSTRACT FROM AUTHOR]

Nineteen CVA9 isolates were obtained between 2010 and 2019 from six provinces of mainland China, using the HFMD surveillance network established in China. Nucleotide sequencing revealed that the full-length VP1 of 19 CVA9 isolates was 906 bases encoding 302 amino acids. The combination of the thresholds of the phylogenetic tree and nucleotide divergence of different genotypes within the same serotype led to a value of 15–25%, and enabled CVA9 worldwide to be categorized into ten genotypes: A–J. The phylogenetic tree showed that the prototype strain was included in genotype A, and that the B, C, D, E, H, and J genotypes disappeared during virus evolution, whereas the F, I, and G genotypes showed co-circulation. Lineage G was the dominant genotype of CVA9 and included most of the strains from nine countries in Asia, North America, Oceania, and Europe. Most Chinese strains belonged to the G genotype, suggesting that the molecular epidemiology of China is consistent with that observed worldwide. The 165 partial VP1 strains (723 nt) showed a mean substitution rate of 3.27 × 10−3 substitution/site/year (95% HPD range 2.93–3.6 × 10−3), dating the tMRCA of CVA9 back to approximately 1922 (1911–1932). The spatiotemporal dynamics of CVA9 showed the spread of CVA9 obviously increased in recent years. Most CVA9 isolates originated in USA, but the epidemic areas of CVA9 are now concentrated in the Asia–Pacific region, European countries, and North America. Recombination analysis within the enterovirus B specie (59 serotypes) revealed eight recombination patterns in China at present, CVB4, CVB5, E30, CVB2, E11, HEV106, HEV85, and HEV75. E14, and E6 may act as recombinant donors in multiple regions. Comparison of temperature sensitivity revealed that temperature-insensitive strains have more amino acid substitutions in the RGD motif of the VP1 region, and the sites T283S, V284M, and R288K in the VP1 region may be related to the temperature tolerance of CVA9. [ABSTRACT FROM AUTHOR]

Coxsackievirus A2 (CV-A2) has emerged as an important etiological agent in the hand, foot, and mouth disease and pathogen spectrum because of its . In the present study, we investigated the evolutionary dynamics of CV-A2 circulating in China. We analyzed a total of 163 entire VP1 sequences of CV-A2, including 74 sequences generated from the present study and 89 sequences collected from the GenBank database. Phylogenetic analysis based on the entire VP1 nucleotide sequences confirmed the persistent circulation of the predominant genotype D in mainland of China since 2008. Cluster analysis grouped the sequences into two distinct clusters, clusters 1 and 2, with most grouped under cluster 2. After 2012, cluster 1 was gradually replaced by cluster 2. Results of Bayesian Markov chain Monte Carlo analysis suggested that multiple lineages of genotype D were transmitted in mainland of China at an estimated evolutionary rate of 6.32×10−3 substitutions per site per year, which is consistent with the global evolutionary rate of CV-A2 (5.82×10−3 substitutions per site per year). Continuous transmission and evolution of CV-A2 resulted in the genetic polymorphism. [ABSTRACT FROM AUTHOR]

Coxsackievirus A2 (CV-A2) has been frequently detected and commonly associated with hand, foot, and mouth disease (HFMD) in China since 2008. However, limited sequences of CV-A2 are currently available. As a result, we have been focusing on the genetic characteristics of CV-A2 in the mainland of China during 2008–2015 based on national HFMD surveillance. In this study, 20 CV-A2 strains were isolated and phylogenetic analyses of the VP1 sequences were performed. Full-length genome sequences of two representative CV-A2 isolates were acquired and similarity plot and bootscanning analyses were performed. The phylogenetic dendrogram indicated that all CV-A2 strains could be divided into four genotypes (Genotypes A–D). The CV-A2 prototype strain (Fleetwood) was the sole member of genotype A. From 2008 to 2015, the CV-A2 strains isolated in China dispersed into two different genotypes (B and D). And the genotype D became the dominant circulating strains in China. Strains isolated in Russia and India from 2005 to 2011 converged into genotype C. Intertypic recombination occurred between the Chinese CV-A2 strains and other enterovirus-A donor sequences. This result reconfirmed that recombination is a common phenomenon among enteroviruses. This study helps expand the numbers of whole virus genome sequence and entire VP1 sequence of CV-A2 in the GenBank database for further researcher. [ABSTRACT FROM AUTHOR]

Since 2008, Mainland China has undergone widespread outbreaks of hand, foot, and mouth disease (HFMD). In order to determine the characteristics of epidemics and enteroviruses (EV) associated with HFMD in Tianjin, in northern China, epidemiological and virological data from routine surveillance were collected and analyzed. In Tianjin, a persistent epidemic of HFMD was demonstrated during 2008-2013, involving 102,705 mild, 179 severe, and 16 fatal cases. Overall, 8234 specimens were collected from 7829 HFMD patients for EV detection during 2008-2013. Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) were the dominant serotypes during 2008-2012, and they were replaced by CV-A6 as the major causative agent in 2013. Phylogenetic analysis based on complete VP1 nucleotide sequences revealed that multiple CV-A6 lineages co-circulated in Tianjin, which grouped together with strains from China and other countries and split into two distinct clusters (clusters 1 and 2). Most Tianjin strains grouped in cluster 1 and were closely related to strains from several eastern and southern provinces of China during 2012 and 2013. Estimates from Bayesian MCMC analysis suggested that multiple lineages had been transmitted silently before the outbreaks at an estimated evolutionary rate of 4.10 × 10 substitutions per site per year without a specific distribution of rate variances among lineages. The sudden outbreak of CV-A6 in Tianjin during 2013 is attributed to indigenous CV-A6 lineages, which were linked to the wide spread of endemic strains around eastern and southern China. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]