title: Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection.
authors: INSERM, U871, Lyon, France. isabelle.vincent@inserm.fr
authors: Isabelle E
authors: IE
authors: Vincent
authors: Claudia
authors: C
authors: Zannetti
authors: Julie
authors: J
authors: Lucifora
authors: Helene
authors: H
authors: Norder
authors: Ulrike
authors: U
authors: Protzer
authors: Pierre
authors: P
authors: Hainaut
authors: Fabien
authors: F
authors: Zoulim
authors: Massimo
authors: M
authors: Tommasino
authors: Christian
authors: C
authors: Trépo
authors: Uzma
authors: U
authors: Hasan
authors: Isabelle
authors: I
authors: Chemin
mesh_terms: D001402:B-Lymphocytes / Q000821:virology; D006528:Carcinoma, Hepatocellular / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000821:virology*; D015536:Down-Regulation / Q000235:genetics; D006515:Hepatitis B virus / Q000276:immunology / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D016898:Interferon-alpha; D008113:Liver Neoplasms / Q000276:immunology; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9 / Q000235:genetics*
chemical_list: D016898:Interferon-alpha; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9