Hepatitis C virus is a weak inducer of interferon alpha in plasmacytoid dendritic cells in comparison with influenza and human herpesvirus type-1.
Plasmacytoid dendritic cells (pDCs) are responsible for the production of type I IFN during viral infection. Viral elimination by IFN-alpha-based therapy in more than 50% of patients chronically infected with hepatitis C virus (HCV) suggests a possible impairment of production of endogenous IFN-alpha 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-alpha 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-alpha production by pDCs in response to cell culture-derived HCV. HCV and noninfectious HCV-like particles inhibited pDC-associated production of IFN-alpha stimulated with Toll-like receptor 9 (TLR9) agonists (CpG-A or HHV-1) but not that of IFN-alpha stimulated with TLR7 agonists (resiquimod or influenza virus). The blockade of TLR9-mediated production of IFN-alpha, effective only when pDCs were exposed to virus prior to or shortly after CpG-A stimulation, was already detectable at the IFN-alpha 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-alpha. This finding is important for our understanding of HCV-DC interaction and immunopathogenesis of HCV infection.
Gondois-Rey
Françoise
F
Institut National de la Santé et de la Recherche MédicaleUMR891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Dental
Clélia
C
Halfon
Philippe
P
Baumert
Thomas F
TF
Olive
Daniel
D
Hirsch
Ivan
I
D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D004705:Endocytosis; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016898:Interferon-alpha; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha