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: Isabelle E Vincent, Claudia Zannetti, Julie Lucifora, Helene Norder, Ulrike Protzer, Pierre Hainaut, Fabien Zoulim, Massimo Tommasino, Christian Trépo, Uzma Hasan, Isabelle Chemin
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e26315 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22046272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon-alpha
• TLR7 protein, human
• TLR9 protein, human
• Toll-Like Receptor 7
• Toll-Like Receptor 9

Topics

• B-Lymphocytes (virology)
• Carcinoma, Hepatocellular (immunology)
• Cells, Cultured
• Dendritic Cells (virology)
• Down-Regulation (genetics)
• Hepatitis B virus (immunology, pathogenicity)
• Hepatitis B, Chronic (immunology)
• Humans
• Immune Evasion
• Interferon-alpha
• Liver Neoplasms (immunology)
• Toll-Like Receptor 7
• Toll-Like Receptor 9 (genetics)