Abstract
Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) remain the predominant pathogens in hand, foot, and mouth disease (HFMD), but the factors underlying the pathogenesis of EV71 and CA16 infections have not been elucidated. Recently, the functions of microRNAs (miRNAs) in pathogen-host interactions have been highlighted. In the present study, we performed comprehensive miRNA profiling in EV71- and CA16-infected human umbilical vein endothelial cells (HUVECs) at multiple time points using high-throughput sequencing. The results showed that 135 known miRNAs exhibited remarkable differences in expression. Of these, 30 differentially expressed miRNAs presented opposite trends in EV71- and CA16-infected samples. Subsequently, we mainly focused on the 30 key differentially expressed miRNAs through further screening to predict targets. Gene ontology (GO) and pathway analysis of the predicted targets showed the enrichment of 14 biological processes, 9 molecular functions, 8 cellular components, and 85 pathways. The regulatory networks of these miRNAs with predicted targets, GOs, pathways, and co-expression genes were determined, suggesting that miRNAs display intricate regulatory mechanisms during the infection phase. Consequently, we specifically analyzed the hierarchical GO categories of the predicted targets involved in biological adhesion. The results indicated that the distinct changes induced by EV71 and CA16 infection may be partly linked to the function of the blood-brain barrier. Taken together, this is the first report describing miRNA expression profiles in HUVECs with EV71 and CA16 infections using high-throughput sequencing. Our data provide useful insights that may help to elucidate the different host-pathogen interactions following EV71 and CA16 infection and offer novel therapeutic targets for these infections.
Highlights
Hand, foot, and mouth disease (HFMD) is a widespread viral illness generally occurring in infants and young children, especially those less than 5 years of age[1]
In order to evaluate the effects of Enterovirus 71 (EV71) and coxsakievirus A16 (CA16) infection on miRNA expression in human umbilical vein endothelial cells (HUVECs), 6 small RNA libraries were constructed and submitted to Illumina sequencing
The read classification of different small RNAs (sRNAs) types-including miRNA, miscellaneous RNA, pseudogenes, ribosomal RNA, small nucleolar RNA, and small nuclear RNA (snRNA) were identified in the samples (S1 Fig), indicating that sRNAs showed dynamic changes in both the EV71- and CA16-infected samples
Summary
Foot, and mouth disease (HFMD) is a widespread viral illness generally occurring in infants and young children, especially those less than 5 years of age[1]. Prior development of HFMD vaccines has almost exclusively focused on EV71, and 3 successfully developed inactivated EV71 vaccines have been approved by the China Food and Drug Administration (CFDA) since 2015[9, 10] These vaccines are effective in providing protection against EV71 infections, their effectiveness may be limited because they cannot induce highly potent and broad cross-protection against various genotypes of other enteroviruses, including CA16[3, 8]. Several severe and fatal cases involving CA16 have recently been reported, and epidemiological surveys indicate that HFMD cases induced by the co-circulation of, co-infection by, or recombination between EV71 and CA16 are increasing[3, 11]. It is our hope that further investigations of the molecular mechanisms of EV71 and CA16 will provide a new strategy for the development of a broad-spectrum HFMD vaccine
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