MiR-16-5p mediates a positive feedback loop in EV71-induced apoptosis and suppresses virus replication

Caishang Zheng,Xianliang Ke,Zhenhua Zheng,Hanzhong Wang,Jianhong Sun,Yuan Zhang,Li Deng,Yan Liu,Chunyu Wei

doi:10.1038/s41598-017-16616-7

Abstract

Enterovirus 71 (EV71) is the predominant causative pathogen of hand-foot-and-mouth disease (HFMD). Contrary to other HFMD-causing enterovirus, EV71 can lead to severe neurological complications, even death. MicroRNAs (miRNAs) are small non-coding RNAs that constitute the largest family of gene regulators participating in numerous biological or pathological processes. We previously reported that miR-16-5p increases with severity of HFMD by investigating the expression patterns of host miRNAs in patients with HFMD. However, the mechanisms by which EV71 induces miR-16-5p expression are not clear, and the interaction between EV71 and miR-16-5p is not yet fully understood. Here, we confirmed EV71-induced expression of miR-16-5p both in vitro and in vivo and show that upregulation of miR-16-5p by EV71 infection may occur at the posttranscriptional level. Moreover, EV71-induced caspase activation facilitates the processing of pri-miR-16-1. We also revealed that miR-16-5p can promote EV71-induced nerve cells apoptosis through activating caspase-3. In addition, we found that miR-16-5p can inhibit EV71 replication. CCNE1 and CCND1, two important cell cycle regulators, play an important role in the suppression of EV71 replication by miR-16-5p. Therefore, miR-16-5p is a positive feedback regulator in EV71-induced apoptosis and a suppressor of virus replication. These results help in understanding the interaction network between miRNA and EV71 infection and provide a potential target for the development of antiviral therapy.

Highlights

Enterovirus 71 (EV71) is a single-positive-stranded RNA virus belonging to the Enterovirus genus of the Picornaviridae family[1,2]
By a histologic HE staining, we observed serious pathological changes in muscle tissue after EV71 infection (Fig. 1f, upper panels). These findings suggest that virus replication mostly occurs in muscle, and relatively low in brain and other organs from this mouse model of EV71 infection
Using NanoString Counter technology, Robert recently found that 44 miRNAs were observed in patients with EV71 infections with a minimum of twofold elevation and 133 miRNAs with a twofold reduction compared with the same miRNAs in healthy controls[60]

Summary

Introduction

Enterovirus 71 (EV71) is a single-positive-stranded RNA virus belonging to the Enterovirus genus of the Picornaviridae family[1,2]. In whole brain and in cervical spinal cord from EV-A71 GZ-CII infected mice. (l,m) The expression of mmu-miR-16-5p in cervical spinal cords form EV-A71 GZ-CII intracerebrally infected mice were analysis by in situ hybridisation (l). Given that a single miRNA may bind up to 100 different transcripts, these miRNAs regulate the expression a large number of genes participating in multiple cellular processes, such as development, differentiation, growth, homeostasis, stress responses, apoptosis and host-pathogen interactions[20,21,22]. One strand of the duplex interacts with the RNA-induced silencing complex (RISC) and guides the RISC to target genes through complementary binding of the seed sequences; the other strand is degraded[33,34]. The study of the interaction of virus and host miRNA will provide molecular insights into viral infection and host gene regulation mechanisms

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Results

Conclusion