Abstract
BackgroundCoxsackievirus A16 (CVA16) and enterovirus 71 (EV71) are two of the major causes of hand, foot and mouth disease (HFMD) world-wide. Although many studies have focused on infection and pathogenic mechanisms, the transcriptome profile of the host cell upon CVA16 infection is still largely unknown.ResultsIn this study, we compared the mRNA and miRNA expression profiles of human embryonic kidney 293T cells infected and non-infected with CVA16. We highlighted that the transcription of SCARB2, a cellular receptor for both CVA16 and EV71, was up-regulated by nearly 10-fold in infected cells compared to non-infected cells. The up-regulation of SCARB2 transcription induced by CVA16 may increase the possibility of subsequent infection of CVA16/EV71, resulting in the co-infection with two viruses in a single cell. This explanation would partly account for the co-circulation and genetic recombination of a great number of EV71 and CVA16 viruses. Based on correlation analysis of miRNAs and genes, we speculated that the high expression of SCARB2 is modulated by down-regulation of miRNA has-miR-3605-5p. At the same time, we found that differentially expressed miRNA target genes were mainly reflected in the extracellular membrane (ECM)-receptor interaction and circadian rhythm pathways, which may be related to clinical symptoms of patients infected with CVA16, such as aphthous ulcers, cough, myocarditis, somnolence and potentially meningoencephalitis. The miRNAs hsa-miR-149-3p and hsa-miR-5001-5p may result in up-regulation of genes in these morbigenous pathways related to CVA16 and further cause clinical symptoms.ConclusionsThe present study elucidated the changes in 293T cells upon CVA16 infection at transcriptome level, containing highly up-regulated SCARB2 and genes in ECM-receptor interaction and circadian rhythm pathways, and key miRNAs in gene expression regulation. These results provided novel insight into the pathogenesis of HFMD induced by CVA16 infection.
Highlights
Coxsackievirus A16 (CVA16) and enterovirus 71 (EV71) are two of the major causes of hand, foot and mouth disease (HFMD) world-wide
Results and discussion mRNA and miRNA expression profiles We analyzed mRNA and miRNA expression profiles based on mRNA-seq and miRNA-seq for CVA16-infected as well as CVA16-non-infected cells to determine how CVA16 infection affects the function of a cell and the related regulatory mechanisms
We examined the impact of infection with CVA16, a major causative pathogen of HFMD, using RNA-seq and miRNA-seq technologies to reveal the associated pathogenic mechanisms at the transcriptome level
Summary
Coxsackievirus A16 (CVA16) and enterovirus 71 (EV71) are two of the major causes of hand, foot and mouth disease (HFMD) world-wide. Foot and mouth disease (HFMD) threatens infants and children globally [1] and is caused by two main pathogens, CVA16 and EV71, both of which are members of the Enterovirus genus in the Picornaviridae family. Our group described that SCARB2-overexpressing cell lines significantly increase their susceptibility to CVA16/EV71 of various genotypes [16], similar susceptibility increasing effect was proved in PSGL-1 overexpressing cells [15, 17]. The infection of these viruses causes the disruption of cellular pathways and events. Cell death and apoptosis in tissues subsequently result in HFMD symptoms
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