The Virion Host Shut-Off (vhs) Protein Blocks a TLR-Independent Pathway of Herpes Simplex Virus Type 1 Recognition in Human and Mouse Dendritic Cells

Christopher R Cotter,John A Blaho,Carolina B López,Thomas M Moran,Jacob S Yount,Marie L Nguyen,Derya Unutmaz

doi:10.1371/journal.pone.0008684

Christopher R Cotter, John A Blaho + Show 5 more

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https://doi.org/10.1371/journal.pone.0008684

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Abstract

Molecular pathways underlying the activation of dendritic cells (DCs) in response to Herpes Simplex Virus type 1 (HSV-1) are poorly understood. Removal of the HSV virion host shut-off (vhs) protein relieves a block to DC activation observed during wild-type infection. In this study, we utilized a potent DC stimulatory HSV-1 recombinant virus lacking vhs as a tool to investigate the mechanisms involved in the activation of DCs by HSV-1. We report that the release of pro-inflammatory cytokines by conventional DC (cDC) during HSV-1 infection is triggered by both virus replication-dependent and replication-independent pathways. Interestingly, while vhs is capable of inhibiting the release of cytokines during infection of human and mouse cDCs, the secretion of cytokines by plasmacytoid DC (pDC) is not affected by vhs. These data prompted us to postulate that infection of cDCs by HSV triggers a TLR independent pathway for cDC activation that is susceptible to blockage by the vhs protein. Using cDCs isolated from mice deficient in both the TLR adaptor protein MyD88 and TLR3, we show that HSV-1 and the vhs-deleted virus can activate cDCs independently of TLR signaling. In addition, virion-associated vhs fails to block cDC activation in response to treatment with TLR agonists, but it efficiently blocked cDC activation triggered by the paramyxoviruses Sendai Virus (SeV) and Newcastle Disease Virus (NDV). This block to SeV- and NDV-induced activation of cDC resulted in elevated SeV and NDV viral gene expression indicating that infection with HSV-1 enhances the cell's susceptibility to other pathogens through the action of vhs. Our results demonstrate for the first time that a viral protein contained in the tegument of HSV-1 can block the induction of DC activation by TLR-independent pathways of viral recognition.

Highlights

Herpes simplex virus (HSV) is a highly efficient pathogen that infects between 60 and 80% of the US population [1]
Herpes Simplex Virus type 1 (HSV-1) Activates conventional DC (cDC) through Replication-Dependent and -Independent Pathways Both of Which Are Inhibited by vhs HSV-1 viruses carrying mutations in the gene encoding the vhs protein, UL41, display a relatively minor reduction in the ability to
Our results demonstrate that during a productive HSV-1 infection the vhs protein carried in the tegument can inhibit the early innate immune response in both human and mouse monocyte-derived cDCs

Summary

Introduction

Herpes simplex virus (HSV) is a highly efficient pathogen that infects between 60 and 80% of the US population [1]. In a primary infection, HSV-infected epithelial cells are shielded from the host immune system long enough to produce progeny virions that infect nearby sensory neurons (reviewed in [2]). The virus enters a latent state in these neurons in which limited gene expression occurs. The host immune response eventually overcomes the viral immune suppressive activities and clears the HSV infected epithelial cells, it is unable to remove latent viral genomes from the neuronal tissues. The host immune response against HSV greatly impacts the severity of primary lesions [3,4,5] and is likely involved in the frequency of reactivation [6,7]

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