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Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell

BACKGROUND: Hepatitis C virus (HCV) can be purified from serum of chronically-infected patients in the form of Lipo-Viro-Particles (LVP), which are triglycerid-rich lipoprotein-like particles containing viral RNA and proteins. Since LVP is a constant feature of chronically infected patients, we aske...

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Autores principales: Agaugué, Sophie, Perrin-Cocon, Laure, André, Patrice, Lotteau, Vincent
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828622/
https://www.ncbi.nlm.nih.gov/pubmed/17389921
http://dx.doi.org/10.1371/journal.pone.0000330
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author Agaugué, Sophie
Perrin-Cocon, Laure
André, Patrice
Lotteau, Vincent
author_facet Agaugué, Sophie
Perrin-Cocon, Laure
André, Patrice
Lotteau, Vincent
author_sort Agaugué, Sophie
collection PubMed
description BACKGROUND: Hepatitis C virus (HCV) can be purified from serum of chronically-infected patients in the form of Lipo-Viro-Particles (LVP), which are triglycerid-rich lipoprotein-like particles containing viral RNA and proteins. Since LVP is a constant feature of chronically infected patients, we asked whether purified LVP could interfere with the immune response by acting directly on dendritic cell (DC) function. METHODS AND FINDINGS: We have analyzed the impact of LVP on the maturation monocyte-derived DC induced by TLR3 or TLR4 ligands. Following incubation with LVP, immature DC supported weak transient HCV-RNA replication and type I IFN synthesis. This, however, did not lead to viral particle production nor to maturation of DC. LVP-treatment prior to TLR3 stimulation by polyI:C only enhanced the secretion of IL-12, IL-6 and TNFα yielding typical mature DC. In contrast, LVP-treated DC activated by the TLR4 ligand LPS yielded phenotypically mature DC with reduced capacity to secrete both pro- and anti-inflammatory cytokines. Their ability to stimulate allogeneic T lymphocytes was strongly affected since activated T cells produced IL-5 and IL-13 instead of IFNγ. Addition of IFNα prevented the effect of LVP on DC function. Restoration of IFNγ secretion by T cells was obtained by blocking ERK activation in DC, while induction of IL-5 and IL-13 secretion was inhibited by blocking the p38-MAPK pathway in DC. CONCLUSIONS: LVP can interfere with TLR4-triggered maturation of DC, inducing a shift in DC function that stimulates Th2 cells instead of Th1, by a mechanism that is ERK- and p38-MAPK-dependent. The effect of LVP on DC polarization was reversed by IFNα, providing an additional rationale for the interferon therapy of chronically-infected patients. By acting on TLR4 pathway with LVP, HCV may thus exploit a natural protective mechanism of the liver and the intestine normally used to control inflammation and immunity to commensal microorganisms.
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spelling pubmed-18286222007-03-28 Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell Agaugué, Sophie Perrin-Cocon, Laure André, Patrice Lotteau, Vincent PLoS One Research Article BACKGROUND: Hepatitis C virus (HCV) can be purified from serum of chronically-infected patients in the form of Lipo-Viro-Particles (LVP), which are triglycerid-rich lipoprotein-like particles containing viral RNA and proteins. Since LVP is a constant feature of chronically infected patients, we asked whether purified LVP could interfere with the immune response by acting directly on dendritic cell (DC) function. METHODS AND FINDINGS: We have analyzed the impact of LVP on the maturation monocyte-derived DC induced by TLR3 or TLR4 ligands. Following incubation with LVP, immature DC supported weak transient HCV-RNA replication and type I IFN synthesis. This, however, did not lead to viral particle production nor to maturation of DC. LVP-treatment prior to TLR3 stimulation by polyI:C only enhanced the secretion of IL-12, IL-6 and TNFα yielding typical mature DC. In contrast, LVP-treated DC activated by the TLR4 ligand LPS yielded phenotypically mature DC with reduced capacity to secrete both pro- and anti-inflammatory cytokines. Their ability to stimulate allogeneic T lymphocytes was strongly affected since activated T cells produced IL-5 and IL-13 instead of IFNγ. Addition of IFNα prevented the effect of LVP on DC function. Restoration of IFNγ secretion by T cells was obtained by blocking ERK activation in DC, while induction of IL-5 and IL-13 secretion was inhibited by blocking the p38-MAPK pathway in DC. CONCLUSIONS: LVP can interfere with TLR4-triggered maturation of DC, inducing a shift in DC function that stimulates Th2 cells instead of Th1, by a mechanism that is ERK- and p38-MAPK-dependent. The effect of LVP on DC polarization was reversed by IFNα, providing an additional rationale for the interferon therapy of chronically-infected patients. By acting on TLR4 pathway with LVP, HCV may thus exploit a natural protective mechanism of the liver and the intestine normally used to control inflammation and immunity to commensal microorganisms. Public Library of Science 2007-03-28 /pmc/articles/PMC1828622/ /pubmed/17389921 http://dx.doi.org/10.1371/journal.pone.0000330 Text en Agaugué et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Agaugué, Sophie
Perrin-Cocon, Laure
André, Patrice
Lotteau, Vincent
Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title_full Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title_fullStr Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title_full_unstemmed Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title_short Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell
title_sort hepatitis c lipo-viro-particle from chronically infected patients interferes with tlr4 signaling in dendritic cell
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828622/
https://www.ncbi.nlm.nih.gov/pubmed/17389921
http://dx.doi.org/10.1371/journal.pone.0000330
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