Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

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Vincent, Isabelle, E | Zannetti, Claudia | Lucifora, Julie | Norder, Helene | Protzer, Ulrike | Hainaut, Pierre | Zoulim, Fabien | Tommasino, Massimo | Trépo, Christian | Hasan, Uzma | Chemin, Isabelle

Edité par CCSD ; Public Library of Science -

International audience. 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-a following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-a 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-a 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-a 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.

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