title: Genetic characterization of human coxsackievirus A6 variants associated with atypical hand, foot and mouth disease: a potential role of recombination in emergence and pathogenicity.
abstract: Human coxsackievirus A6 (CVA6) is an enterically transmitted enterovirus. Until recently, CVA6 infections were considered as being of minor clinical significance, and only rarely aetiologically linked with hand, foot and mouth disease (HFMD) associated with other species A enteroviruses (particularly EV71 and CVA16). From 2008 onwards, however, CVA6 infections have been associated with several outbreaks worldwide of atypical HFMD (aHFMD) accompanied by a varicelliform rash. We recently reported CVA6-associated eczema herpeticum occurring predominantly in children and young adults in Edinburgh in January and February 2014. To investigate genetic determinants of novel clinical phenotypes of CVA6, we genetically characterized and analysed CVA6 variants associated with eczema herpeticum in Edinburgh in 2014 and those with aHFMD in CAV isolates collected from 2008. A total of eight recombinant forms (RFs) have circulated worldwide over the past 10 years, with the particularly recent appearance of RF-H associated with eczema herpeticum cases in Edinburgh in 2014. Comparison of phylogenies and divergence of complete genome sequences of CVA6 identified recombination breakpoints in 2A-2C, within VP3, and between 5' untranslated region and VP1. A Bayesian temporal reconstruction of CVA6 evolution since 2004 provided estimates of dates and the actual recombination events that generated more recently appearing recombination groups (RF-E, -F, -G and -H). Associations were observed between recombination groups and clinical presentations of herpangina, aHFMD and eczema herpeticum, but not with VP1 or other structural genes. These observations provided evidence that NS gene regions may potentially contribute to clinical phenotypes and outcomes of CVA6 infection.
authors.affiliation: Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Gaunt
authors.affiliation: Specialist Virology Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Heli
authors.initials: H
authors.lastname: Harvala
authors.affiliation: Department of Virology, University of Turku, 20520 Turku, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Österback
authors.affiliation: MRC University of Glasgow Centre for Virus Research, 8 Church Street, Glasgow G11 5JR, UK.
authors.forename: Vattipally B
authors.initials: VB
authors.lastname: Sreenu
authors.affiliation: MRC University of Glasgow Centre for Virus Research, 8 Church Street, Glasgow G11 5JR, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Thomson
authors.affiliation: Department of Virology, University of Turku, 20520 Turku, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Waris
authors.affiliation: Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Simmonds
mesh_terms: D000328:Adult; D016000:Cluster Analysis; D004770:Enterovirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification* / Q000472:pathogenicity; D005838:Genotype; D006232:Hand, Foot and Mouth Disease / Q000473:pathology* / Q000821:virology*; D006801:Humans; D007617:Kaposi Varicelliform Eruption / Q000150:complications; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D006113:United Kingdom
chemical_list: D012367:RNA, Viral