Hepatitis C Virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection

Angela Dolganiuc, Serena Chang, Karen Kodys, Pranoti Mandrekar, Gennadiy Bakis, Maureen Cormier, Gyongyi Szabo

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Abstract

IFN-α production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-α-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-α production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-α production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-α and increased TNF-α and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-α and IL-10 induced apoptosis and inhibited IFN-α production in PDCs. Neutralization of TNF-α and/or IL-10 prevented HCV core-induced inhibition of IFN-α production. We identified CD14+ monocytes as the source of TNF-α and IL-10 in the HCV core-induced inhibition of PDC IFN-α production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-α production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-α production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

Original languageEnglish (US)
Pages (from-to)6758-6768
Number of pages11
JournalJournal of Immunology
Volume177
Issue number10
StatePublished - Nov 15 2006
Externally publishedYes

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Chronic Hepatitis C
Virus Diseases
Hepacivirus
Dendritic Cells
Monocytes
Interleukin-10
Apoptosis
Antiviral Agents
Immunity
Hepatitis C virus nucleocapsid protein
Cytokines
Ligands

ASJC Scopus subject areas

  • Immunology

Cite this

Dolganiuc, A., Chang, S., Kodys, K., Mandrekar, P., Bakis, G., Cormier, M., & Szabo, G. (2006). Hepatitis C Virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. Journal of Immunology, 177(10), 6758-6768.

Hepatitis C Virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. / Dolganiuc, Angela; Chang, Serena; Kodys, Karen; Mandrekar, Pranoti; Bakis, Gennadiy; Cormier, Maureen; Szabo, Gyongyi.

In: Journal of Immunology, Vol. 177, No. 10, 15.11.2006, p. 6758-6768.

Research output: Contribution to journalArticle

Dolganiuc, A, Chang, S, Kodys, K, Mandrekar, P, Bakis, G, Cormier, M & Szabo, G 2006, 'Hepatitis C Virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection', Journal of Immunology, vol. 177, no. 10, pp. 6758-6768.
Dolganiuc, Angela ; Chang, Serena ; Kodys, Karen ; Mandrekar, Pranoti ; Bakis, Gennadiy ; Cormier, Maureen ; Szabo, Gyongyi. / Hepatitis C Virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. In: Journal of Immunology. 2006 ; Vol. 177, No. 10. pp. 6758-6768.
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