IFN regulatory factor 1 restricts hepatitis e virus replication by activating STAT1 to induce antiviral IFN-stimulated genes

IFN regulatory factor 1 (IRF1) is one of themost important IFN-stimulated genes (ISGs) in cellular antiviral immunity. Although hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide,howISGs counteract HEVinfection is largely unknown. This study was conducted to investigate the effect of IRF1 onHEVreplication. Multiple cell lines were used in 2models that harbor HEV. In differentHEVcell culture systems, IRF1 effectively inhibitedHEVreplication. IRF1 did not trigger IFN production, and chromatinimmunoprecipitation sequencing data analysis revealed that IRF1 bound to the promoter region of signal transducers and activators of transcription 1 (STAT1). Functional assay confirmed that IRF1 could drive the transcription of STAT1, resulting in elevation of total and phosphorylated STAT1 proteins and further activating the transcription of a panel ofdownstream antiviral ISGs. By pharmacological inhibitors andRNAi-mediated gene-silencing approaches,we revealed that antiviral function of IRF1 is dependent on the JAK-STAT cascade. Furthermore, induction of ISGs and the anti-HEV effect of IRF1 overlapped that of IFNa, but was potentiated by ribavirin. We demonstrated that IRF1 effectively inhibits HEV replication through the activation of the JAK-STAT pathway, and the subsequent transcription of antiviral ISGs, but independent of IFN production. Xu, L., Zhou, X., Wang,W., Wang, Y., Yin, Y., van der Laan, L. J. W., Sprengers,D., Metselaar, H. J., Peppelenbosch, M. P., Pan, Q. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes.

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