Infection of Neuronal Cells by Severe Case Enterovirus A71 Enhances NF-kappaB Activity and Increases NF-kappaB Related Pro-Inflammatory Cytokines

Enterovirus A71 (EV-A71) is the main pathogen of hand-foot-and-mouth disease and sometimes causes neurological disease complications in severe cases. The most recent large EV-A71 outbreak in Taiwan occurred in 2012. We aimed to investigate the gene expression profile of human neuroblastoma cells infected with mild and severe case EV-A71 isolates.EV-A71-infected SK-N-SH cells were sent for RNA sequencing using Illumina Hiseq. Functional gene analysis, qRT-PCR, and luciferase reporter assay were used to investigate the findings obtained from RNA-seq analysis. Expression profile analysis identified 59 significant differentially expressed genes (DEGs) between mild and severe case EV-A71 infection. Gene ontology analysis showed that most of the genes were involved in the regulation of transcription. KEGG pathway enrichment analysis also showed that the DEGs were mainly enriched in the tumor necrosis factor (TNF) and nuclear factor kappa B (NF-kB) signaling. We found that EV-A71 may affect neurons to enhance the disease severity by mediating pro-inflammatory cytokines through NF-kB signaling. Additionally, infection with severe case EV-A71 enhances NF-kB activity, increases proinflammatory cytokines, and reduces cell survival.These results indicate that possible pathogenic mechanisms which were linked to the neuropathogenesis of EV-A71 infection and above genes might be potential biomarkers or antiviral targets for the prevention of neuronal complications in severe EV-A71 infections in the future.