HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

Kai Hu,Qinxue Hu,Rubin Singh,Xinmeng Guan,Mudan Zhang,Sukun Luo,Mei Li,Mariana Barreto,Ming Fu,Jun Wang,Tasnim Chowdhury,Juhua Xiao

doi:10.3389/fimmu.2020.00356

Abstract

It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infection enhances TLR9 expression at both mRNA and protein levels. Such enhancement is virus replication-dependent and CpG-independent, while the HSV-2-mediated upregulation of TLR9 does not activate TLR9 signaling pathway. Mechanistically, a SP1 binding site on TLR9 promoter appears to be essential for HSV-2-induced TLR9 transactivation. Upon HSV-2 infection, SP1 translocates from the cytoplasm to the nucleus, and consequently binds to TLR9 promoter. By using specific inhibitors, the JNK signaling pathway is shown to be involved in the HSV-2-induced TLR9 transactivation, while HSV-2 infection increases the phosphorylation but not the total level of JNK. In agreement, antagonism of JNK signaling pathway inhibits the HSV-2-induced SP1 nuclear translocation. Taken together, our study demonstrates that HSV-2 infection of human genital epithelial cells promotes TLR9 expression through SP1/JNK signaling pathway. Findings in this study provide insights into HSV-2-host interactions and potential targets for immune intervention.

Highlights

Herpes simplex virus type 2 (HSV-2) is a large double-stranded DNA virus that primarily infects genital epithelial cells during the lytic cycle and can eslishes a lifelong latency in the sacral ganglia [1]
Our study has revealed that replicative, but not UV-inactivated HSV-2 induces TLR9 expression in human genital epithelial cells, and this induction is through promoting specificity protein 1 (SP1) binding to TLR9 promoter via JNK signaling pathway
We reveal that HSV-2 infection triggers TLR9 expression in both human genital epithelial cell lines and primary cells

Summary

Introduction

Herpes simplex virus type 2 (HSV-2) is a large double-stranded DNA (dsDNA) virus that primarily infects genital epithelial cells during the lytic cycle and can eslishes a lifelong latency in the sacral ganglia [1]. HSV-2 infection causes clinical manifestations such as genital ulcers, blindness and encephalitis [2, 3]. During its infection and replication, HSV-2 can trigger innate immunity through various recognition signaling pathways including Toll-like receptor (TLR)-dependent and independent pathways [8,9,10]. TLRs are type I transmembrane proteins that recognize pathogen-associated molecular patterns (PAMPs) and signal via MyD88-dependent or TRIF-dependent pathways. Different TLRs can recognize different HSV-2 components. Activation of TLR-mediated signaling pathways leads to the production of inflammatory cytokines

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Results

Conclusion