Multirecombinant Enterovirus A71 Subgenogroup C1 Isolates Associated with Neurologic Disease, France, 2016-2017

Abstract

In 2016, an upsurge of neurologic disease associated with infection with multirecombinant enterovirus A71 subgenogroup C1 lineage viruses was reported in France. These viruses emerged in the 2000s; 1 recombinant is widespread. This virus lineage has the potential to be associated with a long-term risk for severe disease among children.

Keywords: 3Dpol; 5′ UTR; C1 subgenogroup; C1v2015 lineage; EV-A71; France; children; coxsackievirus; enterovirus; enterovirus infection; epidemiologic monitoring; genetic recombination; genomic region P1; most recent common ancestor; neurologic disease; neurologic manifestations; viruses; whole-genome sequencing.

Figure 1

Geographic locations and numbers of enterovirus A71 (EV-A71) subgenogroup C1v2015 infections reported during 2015–2017. A) Countries in which EV-A71 C1v2015 was reported. The year the virus was first reported is indicated. The size of Europe is increased for easier visualization. B) Geographic distribution and number of cases of EV-A71 C1v2015 infection reported in hospitals, by department, France, 2016–2017. C) Geographic distribution of clinical manifestations associated with EV-A71 C1v2015 infection reported in hospitals, by department, France, 2016–2017. The size of a select set of departments is enlarged for easier visualization. HFMD, hand, foot and mouth disease.

Figure 2

Nucleotide similarity and phylogenetic analyses of EV-A71 subgenogroup C1v2015 isolates, France, 2016–2017, constructed to determine temporal origin of C1v2015 lineage. A) Nucleotide similarity patterns between EV-A71 C1v2015 and other EV-A lineages indicate the C1v2015 genome has a mosaic structure. The genome of the virus from patient 10’s throat swab (10|PMB250102|FRA|2016) was used as the query sequence. The similarity plots determined with the other C1v2015 genomes (except 14|COC286037|FRA|2016) were similar. A schematic diagram of the enterovirus genome is shown at the bottom of the panel. Nucleotide similarity was calculated by the sliding window method (window of 300 nt moving every 30 nt). Four genomic modules (labeled at top of panel) with different genetic origins are identified. The 99% CIs of the nucleotide boundaries assessed for the genomic modules (indicated in dark gray) were determined as described in Hassel et al. (11). The 3′ end of module 1 and 5′ end of module 2 were located at the end of the 5′ UTR but were not determined precisely. The 3′ end of module 2 was located between nucleotides 3,532 and 3,722. The 5′ end of module 4 was located at the end of the 3Cpro gene (nucleotides 5,968–6,044). The arrowhead indicates a previously undescribed recombinant lineage of C1v2015 (Appendix Figure 2, https://wwwnc.cdc.gov/EID/article/25/6/18-1460-App1.pdf). B) Phylogenetic tree constructed by using genomic region P1, encoding capsid proteins VP1–VP4, and methods described earlier (11). We performed this analysis with 85 sequences assigned to the EV-A71 C1 and C1v2015 lineages. Tree shows the temporal distribution of lineages, including the emergence of lineage C1v2015. The sequences used as references were labeled with GenBank accession numbers. C) Phylogenetic tree constructed by using the 3Dpol gene encoding the viral RNA polymerase common to C1v2015 and several CV-A strains. The dataset comprised 70 sequences: 24 CV-A (including 5 sequences from this study), 14 EV-A71 C1 (including 6 sequences from this study), 12 publicly available C1v2015, and 20 C1v2015 sequences from this study. Recombination analyses provided no evidence of internal breakpoints within the sequences. N1 represents the time to most recent common ancestor (MRCA) of all included EV-A71 C1v2015 isolates except the virus from patient 14; N2 in panel B represents the MRCA of all EV-A71 C1v2015 isolates, including the virus from patient 14; N2 in panel C represents the MRCA of EV-A71 C1v2015 and its parent C1 lineage; and N3 represents the MRCA of EV-A71 C1v2015 and its parent C1 lineage. Diameters of circles at nodes reflect posterior probability. Branches of trees are color coded according to virus lineage as indicated in panel A. AUS, Australia; AUT, Austria; CAN, Canada; CHE, Switzerland; CHN, China; CMR, Cameroon; C1v2015, enterovirus subgenogroup C1 strain discovered in 2015; CV-A, coxsackievirus A; DEU, Germany; EV-A71C1, enterovirus A71 subgenogroup C1; FRA, France; JPN, Japan; N, node; NLD, the Netherlands; NOR, Norway; MYS, Malaysia; RUS, Russia; THA, Thailand; TKM, Turkmenistan; TWN, Taiwan; USA, United States; UTR, untranslated region; VP, viral protein.