Pseudorabies Virus US3 Protein Inhibits IFN-β Production by Interacting With IRF3 to Block Its Activation.

Jingying Xie,Lei Chen,Yong Zhang,Shujuan Xu,Ruofei Feng,Xiangrong Li,Yingjie Bi,Xiangbo Zhang,Adi Idris

doi:10.3389/fmicb.2021.761282

Abstract

Pseudorabies virus is a typical swine alphaherpesvirus, which can cause obvious neurological disorders and reproductive failure in pigs. It is capable of evading host antiviral immune response. However, the mechanism by which many PRV proteins assist the virus to evade innate immunity is not fully understood. This study identified PRV US3 protein as a crucial antagonistic viral factor that represses interferon beta (IFN-β) expression. A in-depth study showed that US3 protein restricted type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule required for type I IFN induction. Additionally, US3 protein interacted with IRF3, degraded its protein expression to block the phosphorylation of IRF3. These findings suggested a novel strategy utilized by PRV to inhibit IFN-β production and escape the host innate immunity.

Highlights

During a virus infection, host cellular recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and trigger the induction of type I interferons (IFNs) and proinflammatory cytokines to restrict viral replication, clear up of infected cells, and further orchestrate the adaptive immune response to eradicate infected pathogens (Kawai and Akira, 2006; Carpenter et al, 2014; Beachboard and Horner, 2016; Chen et al, 2017)
Given that Herpes simplex virus 1 (HSV-1) US3 can prevent IFN-β activation during infection (Wang et al, 2013; You et al, 2020), we wondered if Pseudorabies virus (PRV) US3 protein performed a similar function via interfering with an IFN-β pathway
PK15 cells were transfected with a US3 expression plasmid for 24 h before ISD transfection to determine the effect of PRV US3 on IFN-β production induced by ISD

Summary

Introduction

Host cellular recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and trigger the induction of type I interferons (IFNs) and proinflammatory cytokines to restrict viral replication, clear up of infected cells, and further orchestrate the adaptive immune response to eradicate infected pathogens (Kawai and Akira, 2006; Carpenter et al, 2014; Beachboard and Horner, 2016; Chen et al, 2017). Stimulator of interferon genes translocate from the ER to the Golgi apparatus to the recruit and phosphorylate TANK-binding kinase 1 (TBK1) and IκB kinase (IKK). These events activate IRF3 and NF-κB to activate type I IFN production (Fitzgerald et al, 2003; Sharma et al, 2003; Sun et al, 2013; Xia et al, 2016). Pseudorabies virus (PRV), a member of the US3 Antagonizes Host Innate Immunity subfamily Alphaherpesvirinae of the family Herpesviridae (Mettenleiter, 2000), causes fatal fever and encephalomyelitis in pigs and susceptible animals (Sun et al, 2016). PRV infection and the disease it causes have brought huge impact on economic for the swine industry

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