Pathogenic Spectrum and CVA6 Gene Characteristics of 882 Severe Hand,Foot,and Mouth Disease from 2012 to 2023
In order to understand the changes in the pathogenic spectrum of severe hand,foot,and mouth disease(HFMD)and the genetic characterization of coxsackievirus A6(CVA6)associated with severe HFMD,this study collected 882 virus isolates from severe HFMD cases isolated by provincial HFMD surveillance network laboratories from 2012 to 2023.Molecular typing of enterovirus was determined by amplifying the VP1 coding region of the virus,and full-length VP1 region amplification and nucleotide sequencing analysis were performed on CVA6,followed by bioinformatics analysis such as maximum likelihood phylogenetic tree and amino acid substitution entropy.The results showed that since 2018,enteroviruses,mainly CVA6 and CVA10,had gradually replaced EV-A71 and CVA16 as the main pathogens causing severe HFMD,accounting for over 50.0％of detected pathogens each year.Except for CVA6 isolated from severe HFMD in 2013,which belonged to the D2 sub-genotype,all CVA6 isolated from severe HFMD after 2013 belonged to the D3a sub-genotype.However,the evolutionary distance between CVA6 sequences isolated in 2019 and those previous isolates were significantly increased,indicating that the VP1 of CVA6 was continuously evolved.In addition,studies on the substitution entropy of amino acid sites showed that VP1-283,which participated in the formation of conformational epitopes,was susceptible to mutation.And this site was mutated from a hydrophilic threonine to a hydrophobic alanine since 2017,leading to the formation of a hydrogen bond between it and VP3-57N as well as VP3-66R,respectively,which may affect the viral infection process.This study clarified the changes in the pathogenic spectrum of severe HFMD in China from 2012 to 2023,exploring the evolutionary characteristics of CVA6 and important amino acid variation characteristics,providing a theoretical basis for the formulation to prevent and control severe HFMD.
Severe hand,foot,and mouth diseasePathogenic spectrumCoxsackievirus A6Phylogenetic analysisAmino acid substitution entropy
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