Downregulation of miR-155-5p facilitates enterovirus 71 replication through suppression of type I IFN response by targeting FOXO3/IRF7 pathway

Abstract

Enterovirus 71 (EV71), the major cause of hand-foot-and-mouth disease (HFMD), has evolved diverse strategies to counter the type I interferon (IFN-I) response during infection. Recently, microRNAs have regulatory roles in host innate immune responses to viral infections; however, whether EV71 escapes the IFN-I antiviral response through regulation of miRNAs remains unclear. Using a microarray assay, microRNA-155-5p (miR-155-5p) was found to be significantly up-regulated in serum from patients with EV71 infection and the increased expression of miR-155-5p was further confirmed in vivo and in vitro in response to EV71 infection. miR-155-5p overexpression suppressed EV71 titers and VP1 protein level, while miR-155-5p inhibition had an opposite result. Moreover, we found that miR-155-5p overexpression enhanced EV71 triggered IFN I production and the expressions of IFN-stimulated genes (ISGs), while inhibition of miR-155-5p suppressed these processes. Furthermore, bioinformatics analysis and luciferase reporter assay demonstrated that miR-155-5p directly targeted forkhead box protein O3 (FOXO3) and negatively regulated FOXO3/IRF7 axis, an important regulatory pathway for type I IFN production during EV71 infection. Inhibition of FOXO3 reversed the effects of miR-155-5p inhibitor on EV71 replication and the type I IFN production. Importantly, in EV71 infection mice, agomir-155-5p injection resulted in a significant reduction of viral VP1 protein expressions in brain and lung tissues, increased IFN-α/β production and increased mice survival rate. In contrast, antagomir-155-5p enhanced EV71 induced these effects. Collectively, our study indicates that weaken miR-155-5p facilitates EV71 replication through suppression of type I IFN response by FOXO3/IRF7 pathway, thereby suggesting a novel strategy for developing effective antiviral therapy.