Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

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.

High-Throughput Sequencing of Putative Novel microRNAs in Rhesus Monkey Peripheral Blood Mononuclear Cells following EV71 and CA16 Infection

“…In a previous study, we found that differentially expressed miRNAs are involved in the regulation of cell-cell junctions in 16HBE cells and HUVECs, but not in PBMCs [1, 16], whereas in PBMCs we found differentially expressed miRNAs associated with nervous system development and modulation of the immune response. This difference may be because 16HBE cells and HUVECs are epithelial cells and endothelial cells, respectively, and that cell-cell junctions play an important role in the barrier function of these cells.…”

“…For example, Cui et al [23] revealed that some miRNAs show differential expression levels following EV71 and CA16 infection, and three key miRNAs (miR-545, miR-324–3p, and miR-143) can be used to distinguish EV71 infection from CA16 infection in patients with HFMD. Furthermore, our previous studies have also demonstrated that there is significant differential expression of known miRNAs in EV71- and CA16-infected human cells [1, 15, 16]. …”

“…HFMD, which is mostly seen in infants and young children under the age of 5 years, is characterized by a maculopapular rash or blisters on the hands, feet, groin, and buttocks, and can also include painful ulcerative lesions of the mouth [1-3]. Although most cases are mild and self-limiting with an average duration of 7 days, approximately 1% of cases can rapidly develop severe and even life-threatening complications, including aseptic meningitis, cerebellar ataxia, poliomyelitis-like paralysis, acute brainstem encephalitis, cardiopulmonary failure, and fulminant neurogenic pulmonary edema associated with high mortality [4].…”

“…In our previous study, we reported that EV71 and CA16 infection can change the expression patterns of miRNAs in various cells, such as human bronchial epithelial (16HBE) cells and human umbilical vein endothelial cells (HUVECs), which are likely to play a role in viral pathogenesis [1, 15]. Hence, in this study, we aimed to further analyze the functions of novel differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) of rhesus monkeys following EV71 and CA16 infection, and to elucidate the possible mechanisms leading to the different outcomes caused by EV71 and CA16 infection.…”

RNA-Seq Data-Mining Allows the Discovery of Two Long Non-Coding RNA Biomarkers of Viral Infection in Humans

“…The human umbilical vein endothelial cells (HUVECs) group contains samples from enterovirus patients (n = 2), coxsackievirus patients (n = 2), and healthy controls (n = 2); GEO accession number: GSE94551 (see [50] for additional information on the samples).…”