Zika Virus Non-Structural Protein NS5 Inhibits the RIG-I Pathway and Interferon Lambda 1 Promoter Activation by Targeting IKK Epsilon.

Lundberg Lundberg,Kakkola Kakkola,Jiang Jiang,Österlund Österlund,Vapalahti Vapalahti,Melén Melén,Khan Khan,Julkunen Julkunen,Westenius Westenius

doi:10.3390/v11111024

Abstract

The Zika virus (ZIKV) is a member of the Flaviviridae family and an important human pathogen. Most pathogenic viruses encode proteins that interfere with the activation of host innate immune responses. Like other flaviviruses, ZIKV interferes with the expression of interferon (IFN) genes and inhibits IFN-induced antiviral responses. ZIKV infects through epithelial barriers where IFN-λ1 is an important antiviral molecule. In this study, we analyzed the effects of ZIKV proteins on the activation of IFN-λ1 promoter. All ZIKV proteins were cloned and transiently expressed. ZIKV NS5, but no other ZIKV protein, was able to interfere with the RIG-I signaling pathway. This inhibition took place upstream of interferon regulatory factor 3 (IRF3) resulting in reduced phosphorylation of IRF3 and reduced activation of IFN-λ1 promoter. Furthermore, we showed that ZIKV NS5 interacts with the protein kinase IKKε, which is likely critical to the observed inhibition of phosphorylation of IRF3.

Highlights

The Zika virus (ZIKV) is a flavivirus that was discovered in 1947 near Entebbe, Uganda.In humans, ZIKV infection has been associated with a mild disease characterized by fever, rash, arthritis, and conjunctivitis [1]
We found that the ZIKV NS5 protein efficiently inhibits RIG-I-induced interferon regulatory factor 3 (IRF3) phosphorylation, leading to a reduction in type I and type III interferon promoter activation
We focused to analyze the functions of individual ZIKV proteins on innate immune pathways

Summary

Introduction

ZIKV infection has been associated with a mild disease characterized by fever, rash, arthritis, and conjunctivitis [1]. The recent epidemic in the Americas in 2013–2015 in an immunologically naïve population revealed that ZIKV can cause severe neurological symptoms, such as Guillain–Barré syndrome and microcephaly [2]. ZIKV is primarily spread by Aedes species mosquitoes, and vertical and sexual transmission among humans was confirmed during the last epidemic. Multiple infection routes of ZIKV are facilitated by its ability to productively infect several types of human cells, such as skin fibroblast and dendritic cells [3], Sertoli cells [4], trophoblast progenitor cells and cytotrophoblasts, as well as placental macrophages [5,6]. ZIKV replicates in human brains and cells of the neuronal origin [7,8]

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Discussion

Conclusion