title: Hepatitis C virus fails to activate NF-κB signaling in plasmacytoid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDCs) respond to viral infection by production of alpha interferon (IFN-α), proinflammatory cytokines, and cell differentiation. The elimination of hepatitis C virus (HCV) in more than 50% of chronically infected patients by treatment with IFN-α suggests that pDCs can play an important role in the control of HCV infection. pDCs exposed to HCV-infected hepatoma cells, in contrast to cell-free HCV virions, produce large amounts of IFN-α. To further investigate the molecular mechanism of HCV sensing, we studied whether exposure of pDCs to HCV-infected hepatoma cells activates, in parallel to interferon regulatory factor 7 (IRF7)-mediated production of IFN-α, nuclear factor kappa B (NF-κB)-dependent pDC responses, such as expression of the differentiation markers CD40, CCR7, CD86, and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and secretion of the proinflammatory cytokines TNF-α and interleukin 6 (IL-6). We demonstrate that exposure of pDCs to HCV-infected hepatoma cells surprisingly did not induce phosphorylation of NF-κB or cell surface expression of CD40, CCR7, CD86, or TRAIL or secretion of TNF-α and IL-6. In contrast, CpG-A and CpG-B induced production of TNF-α and IL-6 in pDCs exposed to the HCV-infected hepatoma cells, showing that cell-associated virus did not actively inhibit Toll-like receptor (TLR)-mediated NF-κB phosphorylation. Our results suggest that cell-associated HCV signals in pDCs via an endocytosis-dependent mechanism and IRF7 but not via the NF-κB pathway. In spite of IFN-α induction, cell-associated HCV does not induce a full functional response of pDCs. These findings contribute to the understanding of evasion of immune responses by HCV.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) UMR891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
authors.forename: Clélia
authors.initials: C
authors.lastname: Dental
authors.forename: Jonathan
authors.initials: J
authors.lastname: Florentin
authors.forename: Besma
authors.initials: B
authors.lastname: Aouar
authors.forename: Francoise
authors.initials: F
authors.lastname: Gondois-Rey
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Nunes
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Ivan
authors.initials: I
authors.lastname: Hirsch
authors.forename: Ruzena
authors.initials: R
authors.lastname: Stranska
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha
references.citation: J Virol. 2003 Mar;77(5):3181-90
references.pmid: 12584342
references.citation: Nat Rev Immunol. 2008 Aug;8(8):594-606
references.pmid: 18641647
references.citation: Blood. 2009 Aug 27;114(9):1794-802
references.pmid: 19553637
references.citation: Nat Med. 2009 Aug;15(8):955-9
references.pmid: 19597505
references.citation: J Immunol. 2006 Jan 1;176(1):248-55
references.pmid: 16365416
references.citation: Immunobiology. 2009;214(9-10):868-76
references.pmid: 19577819
references.citation: Nature. 2005 Apr 21;434(7036):1035-40
references.pmid: 15815647
references.citation: J Clin Invest. 2011 Mar;121(3):1088-101
references.pmid: 21339641
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7431-6
references.pmid: 20231459
references.citation: Hepatology. 2008 Mar;47(3):799-809
references.pmid: 18203148
references.citation: Blood. 2008 Nov 1;112(9):3713-22
references.pmid: 18698004
references.citation: J Immunol. 2002 Sep 15;169(6):3447-58
references.pmid: 12218168
references.citation: Sci Signal. 2009 Sep 01;2(86):pl3
references.pmid: 19724061
references.citation: PLoS Pathog. 2011 Feb;7(2):e1001284
references.pmid: 21379343
references.citation: Virology. 2005 Dec 20;343(2):256-66
references.pmid: 16278001
references.citation: AIDS. 2000 Oct 20;14(15):2239-46
references.pmid: 11089611
references.citation: J Exp Med. 2007 Oct 1;204(10):2423-37
references.pmid: 17893202
references.citation: Annu Rev Immunol. 2005;23:275-306
references.pmid: 15771572
references.citation: PLoS Pathog. 2008 Oct;4(10):e1000193
references.pmid: 18974865
references.citation: PLoS One. 2009;4(2):e4319
references.pmid: 19183807
references.citation: Gastroenterology. 2001 Feb;120(2):512-24
references.pmid: 11159892
references.citation: Science. 1999 Jun 11;284(5421):1835-7
references.pmid: 10364556
references.citation: Nature. 2008 Mar 13;452(7184):234-8
references.pmid: 18305481
references.citation: J Gen Virol. 2007 Sep;88(Pt 9):2495-2503
references.pmid: 17698659
references.citation: Blood. 2009 Aug 20;114(8):1518-27
references.pmid: 19528537
references.citation: Trends Immunol. 2010 Oct;31(10):391-7
references.pmid: 20832362
references.citation: J Exp Med. 2002 Jun 3;195(11):1507-12
references.pmid: 12045249
references.citation: Lancet. 2001 Sep 22;358(9286):958-65
references.pmid: 11583749
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
references.pmid: 18467494
references.citation: J Virol. 2009 Apr;83(8):3719-33
references.pmid: 19176632
references.citation: Nature. 2009 Oct 8;461(7265):798-801
references.pmid: 19759533
references.citation: J Gastroenterol. 2011 Apr;46(4):432-47
references.pmid: 21327958
references.citation: Hepatology. 2008 Feb;47(2):385-95
references.pmid: 18064579
references.citation: Science. 2010 Sep 17;329(5998):1530-4
references.pmid: 20847273
references.citation: J Immunol. 2010 Mar 1;184(5):2518-27
references.pmid: 20100933
references.citation: N Engl J Med. 2002 Sep 26;347(13):975-82
references.pmid: 12324553
references.citation: Dev Biol Stand. 1999;98:39-51; discussion 73-4
references.pmid: 10494958
references.citation: J Immunol. 2008 Nov 15;181(10):6747-56
references.pmid: 18981092
references.citation: J Virol. 2004 Jun;78(11):5867-74
references.pmid: 15140984