Genetic Diversity Analysis of Coxsackievirus A8 Circulating in China and Worldwide Reveals a Highly Divergent Genotype

Abstract

Coxsackievirus A8 (CV-A8) is one of the pathogens associated with hand, foot and mouth disease (HFMD) and herpangina (HA), occasionally leading to severe neurological disorders such as acute flaccid paralysis (AFP). Only one study aimed at CV-A8 has been published to date, and only 12 whole-genome sequences are publicly available. In this study, complete genome sequences from 11 CV-A8 strains isolated from HFMD patients in extensive regions from China between 2013 and 2018 were determined, and all sequences from GenBank were retrieved. A phylogenetic analysis based on a total of 34 complete VP1 sequences of CV-A8 revealed five genotypes: A, B, C, D and E. The newly emerging genotype E presented a highly phylogenetic divergence compared with the other genotypes and was composed of the majority of the strains sequenced in this study. Markov chain Monte Carlo (MCMC) analysis revealed that genotype E has been evolving for nearly a century and somehow arose in approximately 2010. The Bayesian skyline plot showed that the population size of CV-A8 has experienced three dynamic fluctuations since 2001. Amino acid residues of VP1100N, 103Y, 240T and 241V, which were embedded in the potential capsid loops of genotype E, might enhance genotype E adaption to the human hosts. The CV-A8 whole genomes displayed significant intra-genotypic genetic diversity in the non-capsid region, and a total of six recombinant lineages were detected. The Chinese viruses from genotype E might have emerged recently from recombining with European CV-A6 strains. CV-A8 is a less important HFMD pathogen, and the capsid gene diversity and non-capsid recombination variety observed in CV-A8 strains indicated that the constant generation of deleterious genomes and a constant selection pressure against these deleterious mutations is still ongoing within CV-A8 quasispecies. It is possible that CV-A8 could become an important pathogen in the HFMD spectrum in the future. Further surveillance of CV-A8 is greatly needed.

Characterizing enterovirus C96 genome and phylodynamics analysis

“…23 Since then, CVA16, CVA6, CVA4, CVA2, CVA8, and CVA9 have been molecularly typed based on a 15%-25% threshold for nucleotide differences. [44][45][46][47][48] In this study, despite fewer EV-C96 sequences, the coding region of VP1 region had a higher nucleotide genetic distance (0.012-0.305), which exceeded the critical value of 0.25 for genotyping. In all, EV-C96 could be classified into 15 genogroups, and the Chinese strains were distributed into 9 genogroups, indicating its large genetic variation.…”

Natural intertypic and intratypic recombinants of enterovirus 71 from mainland China during 2009–2018: a complete genome analysis

“…The breakpoint at 2A region is a recombination hot spot in enterovirus [ 5 ]. Based on previous reports [ 12 , 33 , 34 ], we speculated that the 2A region for the CA8 serotype might be prone to recombination events with respect to gene fragment exchange.…”

“…Since then, numerous RNA virus recombinants have been reported, including picornaviruses, coronaviruses, and alphaviruses [7][8][9][10]. Previous studies on enterovirus have also suggested extensive recombination between and within enterovirus [11][12][13][14]. The recombination events of enterovirus have been observed in many countries, such as Japan, Malaysia, Singapore, Thailand, Netherlands, and China [15][16][17][18][19][20][21][22][23].…”

Genetic characterization and molecular epidemiology of Coxsackievirus A12 from mainland China during 2010–2019

“…This leads to the emergence of lineages with altered characteristics. In addition, recombination can generate chimeric molecules from parental genomes of different phylogenetic origins and may also help enteroviruses to acquire combined advantageous features from various genomes during the process of evolution ( Lukashev et al, 2004 ; Bouslama et al, 2007 ; Zhang et al, 2015 ; Song et al, 2020 ). This may prompt the evolution of CVA12 into a new recombinant with higher virulence and transmissibility.…”

“…Due to cumulative mutations and/or recombination, enteroviruses have a high degree of genetic diversity and produce populations with related sequences ( Muslin et al, 2019 ). The coding region of VP1 contains the most important antigen-specific neutralization sites of enterovirus (EV) capsid proteins, which is serotype specific ( Song et al, 2020 ). Most genotyping of enterovirus is based on sequence analysis of VP1, such as EV-A71 ( Mcwilliam Leitch et al, 2012 ), CVA16 ( Zhang et al, 2010a ), CVA6 ( He et al, 2013 ), EV-B80 ( Han et al, 2018 ), CVA2 ( Yang et al, 2018 ) and CVB1 ( Kim et al, 2013 ).…”