Abstract

Plasmacytoid dendritic cells (pDCs) are responsible for the production of type I IFN during viral infection. Viral elimination by IFN-α-based therapy in more than 50% of patients chronically infected with hepatitis C virus (HCV) suggests a possible impairment of production of endogenous IFN-α by pDCs in infected individuals. In this study, we investigated the impact of HCV on pDC function. We show that exposure of pDCs to patient serum- and cell culture-derived HCV resulted in production of IFN-α by pDCs isolated from some donors, although this production was significantly lower than that induced by influenza and human herpesvirus type 1 (HHV-1). Using specific inhibitors we demonstrate that endocytosis and endosomal acidification were required for IFN-α production by pDCs in response to cell culture-derived HCV. HCV and noninfectious HCV-like particles inhibited pDC-associated production of IFN-α stimulated with Toll-like receptor 9 (TLR9) agonists (CpG-A or HHV-1) but not that of IFN-α stimulated with TLR7 agonists (resiquimod or influenza virus). The blockade of TLR9-mediated production of IFN-α, effective only when pDCs were exposed to virus prior to or shortly after CpG-A stimulation, was already detectable at the IFN-α transcription level 2 h after stimulation with CpG-A and correlated with down-regulation of the transcription factor IRF7 expression and of TLR9 expression. In conclusion, rapidly and early occurring particle–host cell protein interaction during particle internalization and endocytosis followed by blockade of TLR9 function could result in less efficient sensing of HCV RNA by TLR7, with impaired production of IFN-α. This finding is important for our understanding of HCV-DC interaction and immunopathogenesis of HCV infection.

Highlights

  • The Plasmacytoid dendritic cells (pDCs) obtained from patients with chronic hepatitis C virus (HCV) infection were exposed to synthetic stimulators of TLR7 or Toll-like receptor 9 (TLR9) in the absence of HCV, more recent studies investigated the effects of TLR7 or TLR9 ligands on pDCs purified from healthy donors in the presence of cell culture-prepared HCV (HCVcc) [21,23]

  • In contrast to these earlier studies, we show here that exposure of pDCs to HCV results in production of IFN-a by pDCs isolated from some donors, this production is significantly lower than that induced by influenza and human herpesvirus type 1 (HHV-1)

  • Stimulation with the natural agonist of TLR7 influenza virus significantly increased the expression of CD80, CD83, and CCR7, whereas stimulation with the natural agonist of TLR9 HHV-1 significantly increased the expression of CD86, CD83, and CCR7

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Summary

Introduction

Plasmacytoid dendritic cells (pDCs) are a highly specialized subset of dendritic cells that function as sentinels for viral infection and are responsible for production of large amounts of type I IFN during viral infection [1,2,3]. pDCs are able to detect genetic material of virus particles after their degradation in endosomal compartments via interaction with Toll-like receptors (TLR) [4]. pDCs are able to detect DNA of inactivated human herpesvirus types 1 (HHV-1) and 2 (HHV-2) via TLR9 (AAQ89443) [5,6], and they are able to detect single-stranded RNA of inactivated influenza virus and of HIV-1 via TLR7 (AAQ88659) [7,8,9,10]. The pDCs obtained from patients with chronic HCV infection were exposed to synthetic stimulators of TLR7 or TLR9 in the absence of HCV, more recent studies investigated the effects of TLR7 or TLR9 ligands on pDCs purified from healthy donors in the presence of cell culture-prepared HCV (HCVcc) [21,23] These reports have shown that exposure of pDCs from healthy donors to HCVcc is not followed by expression of the HCVcc genome and viral replication, that HCVcc does not induce pDC-associated production of IFN-a and cell differentiation [21,23], and that, in addition, HCVcc blocks IFNa production mediated via TLR9 [23]

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