Upregulation of nuclear factor E2-related factor 2 (Nrf2) represses the replication of herpes simplex virus type 1

Li Zhang,Hui Wang,Ying Li,Jiao Wang,Zhan Wang,Hongtu Liu

doi:10.1186/s12985-021-01733-7

Abstract

BackgroundNuclear factor E2-related factor 2 (Nrf2) is an important transcription factor which plays a pivotal role in detoxifying reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. However, the role of Nrf2 in Herpes Simplex Virus type 1 (HSV-1) infection is still unclear. In this study, the interaction between the Nrf2 and HSV-1 replication was investigated.MethodsThe levels of oxidative stress was monitored by using 8-hydroxy-2'-deoxyguanosine (8-OHdG) ELISA kits, and the dynamic changes of Nrf2-antioxidant response element (Nrf2-ARE) pathway were detected by Western Blot. The effect of Nrf2-ARE pathway on the regulation of HSV-1 proliferation was analyzed by Western Blot, Real-Time PCR and TCID50 assay.ResultsHSV-1 infection induced oxidative stress. Nrf2 was activated, accompanied by the increase of its down-stream antioxidant enzyme heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) in the early stage of HSV-1 infection. The proliferation of HSV-1 was inhibited by overexpression of Nrf2 or treatment with its activator tert-Butylhydroquinone (tBHQ). On the contrary, silencing of Nrf2 promotes virus replication. HO-1 is involved in the regulation of IFN response, leading to efficient anti-HSV-1 effects.ConclusionOur observations indicate that the Nrf2-ARE pathway activates a passive defensive response in the early stage of HSV-1 infection. Targeting the Nrf2 pathway demonstrates the potential for combating HSV-1 infection.

Highlights

Herpes Simplex Virus type 1 (HSV-1) is a prevalent and important human pathogen with a worldwide seroprevalence of more than 80% in adults
Blot was performed to identify the expression of Nuclear factor E2-related factor 2 (Nrf2) (Abcam, USA), Kelch-like ECH-associated protein 1 (Keap1) (Abcam, USA), heme oxygenase-1 (HO-1) (CST, USA), NAD(P)H quinone oxidoreductase 1 (NQO1) (CST, USA) and virus protein ICP4 (Abcam, USA)
HSV‐1 infection induced oxidative stress and Nrf2 was activated in the early stage of HSV‐1 infection To determine whether oxidative stress was induced by HSV-1 infection, the levels of 8-OHdG, a measure of oxidative stress, was monitored after HSV-1 infection at an multiplicities of infection (MOI) of 1

Summary

Introduction

Herpes Simplex Virus type 1 (HSV-1) is a prevalent and important human pathogen with a worldwide seroprevalence of more than 80% in adults. Oxidative stress-induced by viral infection is one of the major pathogenic mechanisms and may contribute to Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. Regulation of the Nrf2-antioxidant defense systems is involved in viral susceptibility, virus-associated inflammation, and immune clearance. Nuclear factor E2-related factor 2 (Nrf2) is an important transcription factor which plays a pivotal role in detoxifying reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. The role of Nrf in Herpes Simplex Virus type 1 (HSV-1) infection is still unclear. The interaction between the Nrf and HSV-1 replication was investigated

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