Title

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

Student Author(s)

Serena S. Chang

Academic Program

Immunology and Microbiology

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Medicine, Division of Gastroenterology

Publication Date

2006-11-04

Document Type

Article

Disciplines

Immunology and Infectious Disease

Abstract

IFN-alpha production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-alpha-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-alpha 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-alpha 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-alpha and increased TNF-alpha and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-alpha and IL-10 induced apoptosis and inhibited IFN-alpha production in PDCs. Neutralization of TNF-alpha and/or IL-10 prevented HCV core-induced inhibition of IFN-alpha production. We identified CD14+ monocytes as the source of TNF-alpha and IL-10 in the HCV core-induced inhibition of PDC IFN-alpha production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-alpha 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-alpha production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

DOI of Published Version

10.4049/jimmunol.177.10.6758

Source

J Immunol. 2006 Nov 15;177(10):6758-68.

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

Related Resources

Link to article in PubMed

PubMed ID

17082589

Link to Full Text

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