microRNA-4516 Contributes to Different Functions of Epithelial Permeability Barrier by Targeting Poliovirus Receptor Related Protein 1 in Enterovirus 71 and Coxsackievirus A16 Infections

Abstract

Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) remain the predominant etiological agents of hand, foot, and mouth disease (HFMD). The clinical manifestations caused by the two viruses are obviously different. CV-A16 usually triggers a repeated infection, and airway epithelial integrity is often the potential causative factor of respiratory repeated infections. Our previous studies have demonstrated that there were some differentially expressed miRNAs involved in the regulation of adhesion function of epithelial barrier in EV-A71 and CV-A16 infections. In this study, we compared the differences between EV-A71 and CV-A16 infections on the airway epithelial barrier function in human bronchial epithelial (16HBE) cells and further screened the key miRNA which leaded to the formation of these differences. Our results showed that more rapid proliferation, more serious destruction of 16HBE cells permeability, more apoptosis and disruption of intercellular adhesion-associated molecules were found in CV-A16 infection as compared to EV-A71 infection. Furthermore, we also identified that microRNA-4516 (miR-4516), which presented down-regulation in EV-A71 infection and up-regulation in CV-A16 infection was an important regulator of intercellular junctions by targeting Poliovirus receptor related protein 1(PVRL1). The expressions of PVRL1, claudin4, ZO-1 and E-cadherin in CV-A16-infected cells were significantly less than those in EV-A71-infected cells, while the expressions of these proteins were subverted when pre-treated with miR-4516-overexpression plasmid in EV-A71 infected and miR-4516-knockdown plasmid in CV-A16 infected 16HBE cells. Thus, these data suggested that the opposite expression of miR-4516 in EV-A71 and CV-A16 infections might be the initial steps leading to different epithelial impairments of 16HBE cells by destroying intercellular adhesion, which finally resulted in different outcomes of EV-A71 and CV-A16 infections.

Airway tight junctions as targets of viral infections

“… 81 , 82 Transmission usually happens through the respiratory droplets, but can alsooccur through fecal-oral contamination. 25 , 26 , 81 , 83 , 84 …”

MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease

“…Interestingly, overexpression of miR-4516 in human keratinocytes inhibits cell motility and proliferation through downregulation of genes involved in cytoskeletal reorganisation, and in response to PUVA (8-methoxypsoralen plus UVA), miR-4516 also mediates inactivation of AKT/mTOR pathway followed by suppression of cell migration 16 17. Moreover, miR-4516 modulates intercellular junctions by targeting PVRL1 (poliovirus receptor related protein 1) 27…”

Bioinformatics analysis of key micro-RNAs and mRNAs under hand, foot, and mouth disease virus infection

“…However, these two viruses not necessarily have similar effects, in despite that both viruses belong to members of the genus Enterovirus. For example, Chinese scholars identified that miR-4516 presented down-regulation in EV71 infection and upregulation in CA16 infection, and it was an important regulator of intercellular junctions by targeting PVRL1 [13]. Liu et al had analyzed microRNA profiles and acquired diverse outcomes induced by EV71 and CA16 infection [15].…”

“…Previous studies have explored the disordered signals in different aspect, such as inflammatory profiles in cytokine expression [5,6], long non-coding RNA (lncRNA) profiles [7], and immune cell changes [8]. It is conceivable and has been supported that HFMD patients may exhibit changes in expression profiles of microRNAs and mRNAs, especially derived from blood samples [9][10][11][12][13][14][15][16][17][18][19]. In addition, comprehensive understanding of HFMD-related expression profiles and identification key markers may provide huge diagnostic and prognostic values.…”