HSV Infection Induces Production of ROS, which Potentiate Signaling from Pattern Recognition Receptors: Role for S-glutathionylation of TRAF3 and 6

Regina Gonzalez-Dosal,Kristy A Horan,John J Mieyal,Søren R Paludan,Rune Hartmann,Zhijian J Chen,Stine H Rahbek,Hidenori Ichijo,William J Britt

doi:10.1371/journal.ppat.1002250

Abstract

The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection.

Highlights

The innate immune response constitutes the first line of defense against invading pathogens, and relies on pattern recognition receptors (PRR)s for detection of infections through recognition of either molecular structures specific for non-self, or aberrant localization of molecules used by both host and microbe [1,2]
In this article we show that Herpes simplex virus (HSV) infection leads to production of reactive oxygen species (ROS), and that ROS play a critical role in activation of innate immune responses to these viruses
We show that ROS stimulate glutathionylation of the signaling molecules TRAF3 and 6, which promotes redox-sensitive signaling

Summary

Introduction

The innate immune response constitutes the first line of defense against invading pathogens, and relies on pattern recognition receptors (PRR)s for detection of infections through recognition of either molecular structures specific for non-self, or aberrant localization of molecules used by both host and microbe [1,2]. Toll-like receptors (TLR)s are membrane-bound PRRs localized in the plasma membrane and endosomes, which recognize microbes at these sites. Other families of PRRs are localized in the cytoplasm, such as Retinoic acid-inducible gene (RIG)-I-like receptors (RLR)s which detect cytosolic RNA [1,2]. Innate recognition of HSV involves a large spectrum of PRRs, which together orchestrate the innate immune response to infections by this virus [reviewed in ref. Innate recognition of HSV involves a large spectrum of PRRs, which together orchestrate the innate immune response to infections by this virus [reviewed in ref. 14]

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Conclusion