Enterovirus D: A Small but Versatile Species

Figures

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  Figure 1. Phylogenetic trees constructed from complete genomes (A) and VP1 (B) of members of the Enterovirus D species. Both trees were rooted on porcine enterovirus 8 (AF406813), not shown. Only VP1 sequence was available for EV-D120, excluding this genotype from (A). Phylogenetic trees were constructed with PhyML using the Smart Model Selection, based on ungapped multiple sequence alignments produced with Muscle [14,15,16,17]. GenBank accession number are detailed in parentheses for each virus except for EV-D68 that includes several strains (AY426531, AB601882.2, AB601883.2, JX070222.1, JX10184.1, KF726085, KM851231.1, KM892500.1, KP240936, KP745755.1, KP745766.1, KP745767.1, KT285319.1, MK105982.1, MN240505, MN245981).

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  Figure 2. Structure of the cis-acting elements present in EV-D genomes: 5′ CL (A), 5′ IRES with its respective topology tree (B), 3′ UTR (C), and cre (D). Contemporary EV-D68, EV-D68 Fermon, EV-D94, EV-D70, and EV-D111 were included. The RNA fragments were extracted using the AliView [17] sequence alignment editor and then were simultaneously folded and aligned using LocARNA from Freiburg RNA tools. The sequence alignment of the different regions is available in Supplementary Figure S1.

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  Figure 3. Enterovirus D cleavage recognition sequences of the 2A and 3C proteases. Comparison between the EV 2A and 3C cleavage sequence (in the table as “2A cleavage sequence” and “3C cleavage sequence”, mentioned in the text and reviewed in Reference [41]) and the sequence observed in EV-D members at the different cleavage sites across the polyprotein. Based on the sequences of EV-D68 (AY426531), EV-D94 (EF107097 and DQ916376), EV-D70 (DQ201177 and D00820), and EV-D111 (MW384881). The critical positions for recognition by the viral proteases are in blue (residues listed in the table), while the less conserved positions are in grey (* undefined residues).

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  Figure 4. Known binding/attachment receptors identified to date for the Enterovirus D species. EV-D68 was identified to utilize α-2,3 and α-2,6 SAs for attachment and ICAM-5 as a binding receptor. The host factor PLA2G16 aids to initiate the uncoating of EV-D68 into infected cells in a SA-dependent manner. EV-D70 utilizes α-2,3 SAs and DAF1/CD55 as binding and attachment receptors, respectively, while EV-D94 has affinity to α-2,3 SAs and α-2,6 SAs. Receptors for other EVs of this class, namely EV-D111 and EV-D120, have not been identified to date. sGAG are not shown as they may not be true receptors in vivo. Created with BioRender.com, accessed on 15 July 2021.

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  Figure 5. Tropism and associated symptoms of human enterovirus infections. The most commonly reported symptoms associated to each EV infection in the human host are depicted, grouped by organ. Highlighted in blue are the members of the Enterovirus D species. All EV-Ds infecting humans have been associated with neural infections, although a causal link remains to be demonstrated. Their primary replication site is reported to be initiated either in the eye (EV-D70), respiratory tract (EV-D68), or gut (EV-D94 and EV-D111). Even though there is an association between *viruses found in stools, no gastro-intestinal symptoms are reported. Abbreviations: EV, enterovirus; RV, rhinovirus; CV, coxsackievirus; PV, poliovirus; and E, echovirus. Adapted from: “Expression of ACE2 Receptor in Human Host Tissues” by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates, accessed on 15 July 2021.