Genetic characterisation of human Coxsackievirus A6 variants associated with atypical hand, foot and mouth disease; a potential role of recombination in emergence and pathogenicity

Coxsackievirus A6 (CAV6) is an enterically transmitted enterovirus. Until recently, CAV6 infections have been 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 enterovirus 71 and CAV16). From 2008 onwards, however, CAV6 infections have been associated with several outbreaks worldwide of atypical HFMD (aHFMD) accompanied by a varicelliform rash. We recently reported CAV6-associated eczema herpeticum (EH) occurring predominantly in children and young adults in Edinburgh in January - February, 2014. To investigate genetic determinants of novel clinical phenotypes of CAV6, we genetically characterised and analysed CAV6 variants associated with EH in Edinburgh, 2014 and those with aHFMD in CAV isolates collected from 2008. A total of eight recombinant forms have circulated worldwide over the past 10 years, with particularly recent appearance of recombinant form H (RF-H) associated with EH cases in Edinburgh in 2014. Comparison of phylogenies and divergence of complete genome sequences of CAV6 identified recombination breakpoints in 2A-2C, within VP3 and between VP1 and the 5'untranslated region. A Bayesian temporal reconstruction of CAV6 evolution since 2004 provided estimates of dates and the actual recombination events that generated more recently appearing RFs (-E, -F, -G and -H). Associations were observed between recombination groups and clinical presentations of herpangina, aHFMD and EH, but not with VP1 or other structural genes. These observations provide evidence that NS gene regions may potentially contribute to clinical phenotypes and outcomes of CAV6 infection.