Abstract
The elimination of hepatitis C virus (HCV) in > 50% of chronically infected patients by treatment with IFN-α suggests that plasmacytoid dendritic cells (pDCs), major producers of IFN-α, play an important role in the control of HCV infection. However, despite large amounts of Toll-like receptor 7-mediated IFN-α, produced by pDCs exposed to HCV-infected hepatocytes, HCV still replicates in infected liver. Here we show that HCV envelope glycoprotein E2 is a novel ligand of pDC C-type lectin immunoreceptors (CLRs), blood DC antigen 2 (BDCA-2) and DC-immunoreceptor (DCIR). HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the crosslinking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles. Thus, negative interference of CLR signaling triggered by cell-free HCV particles with Toll-like receptor signaling triggered by cell-associated HCV results in the inhibition of the principal pDC function, production of IFN.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Carcinoma, Hepatocellular / immunology
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / virology
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Cell Line, Tumor
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Cells, Cultured
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Chlorocebus aethiops
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / virology
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Extracellular Signal-Regulated MAP Kinases / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flow Cytometry
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Hepacivirus / immunology
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Hepacivirus / metabolism
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Hepacivirus / physiology
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Host-Pathogen Interactions / immunology
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Humans
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Interferons / immunology*
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Interferons / metabolism
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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Ligands
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Liver Neoplasms / immunology
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Liver Neoplasms / pathology
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Liver Neoplasms / virology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Phosphorylation
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Protein Binding
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology*
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Receptors, Immunologic / metabolism
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Toll-Like Receptor 7 / immunology
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Toll-Like Receptor 7 / metabolism
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Viral Envelope Proteins / immunology*
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Viral Envelope Proteins / metabolism
Substances
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CLEC4A protein, human
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CLEC4C protein, human
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Lectins, C-Type
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Ligands
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Membrane Glycoproteins
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Receptors, Immunologic
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Toll-Like Receptor 7
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Viral Envelope Proteins
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glycoprotein E2, Hepatitis C virus
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Interferons
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases