Lambda-interferons inhibit herpes simplex virus type 2 replication in human cervical epithelial cells by activating the JAK/STAT pathway

Abstract

SUMMARY: Herpes simplex virus type 2 (HSV-2) is associated with a variety of diseases that are health problems worldwide. Our early study showed that lambda-interferons (IFN-λs), induced by the activation of the Toll-like receptor 3 and retinoic acid-inducible protein I signaling pathways, contribute to inhibition of HSV-2 replication in human cervical epithelial cells. However, anti-HSV-2 mechanisms and specific differences in signaling transduction by different IFN-λs in human cervical epithelial cells remain unclear. In this study, we demonstrated potent inhibition of HSV-2 replication by IFN-λs without cytotoxicity. Investigation of the underlying mechanism(s) showed that IFN-λs induced expression of IFN-stimulated genes (ISGs) and enhanced the expression of several pattern recognition receptors (PRRs). Among the IFN-λs, IFN-λ3 induced higher levels of ISG and PRR expression. In addition, IFN-λs upregulated a number of genes that encode components of the Janus kinase signal transducers and activators of transcription (JAK/STAT) signaling pathway. Inhibition of the JAK/STAT signaling pathway by a JAK inhibitor abolished IFN-λ-mediated anti-HSV-2 activity and induction of ISGs and PRRs, whereas the induction of ISGs and PRRs by IFN-λs was not compromised by HSV-2 infection. These findings provide further experimental evidence that IFN-λs have therapeutic potential for HSV-2 infections.