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.

Impaired monocyte‐macrophage functions and defective toll‐like receptor signaling in hepatitis E virus‐infected pregnant women with acute liver failure

“…39 Both hepatitis B and C viruses efficiently impair LR9 signaling in DCs and contribute to disease pathogenesis. 9,40 Recently, weak TLR response in HEV infection during pregnancy was reported; however, the study compared pregnant and nonpregnant women with HEV infection, but not those with or without liver failure. 41 This novel study is the first report showing the involvement of macrophages and TLR signaling defects in monocytes and macrophages in ALF patients during pregnancy (Fig.…”

“…There were significant differences in the ALT, aspartate aminotransferase (AST), bilirubin, and INR values in ALF-E(P) and in AVH-E(P) patients compared to HC(P) ( Table 1). All patients in the ALF-E(P) group were detected during late pregnancy in the third trimester (week 32; range, weeks [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. None of the AVH-E patients developed HE during the follow-up period.…”

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

“…15 During chronic HBV infection, pDCs display reduced TLR9 expression and an impaired ability to secrete IFN-a after ex vivo stimulation with TLR9 ligands. 8,29,30 HBV virions were able to directly inhibit TLR9 transcription through downregulation of TLR9 promoter activity, by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to suppress IFN-a production. 8 Along the same lines, Xu et al 31 demonstrated that HBsAg can inhibit TLR9-mediated IRF7 expression and nuclear translocation through upregulation of SOCS-1 expression.…”

“…Recent studies have indicated that TLR expression in peripheral immune cells, liver immune cells, and hepatocytes changed during chronic HBV infection accompanied by impaired TLR functions. [6][7][8][9] Meanwhile, TLR-mediated innate immune responses have been shown to inhibit HBV replication in hepatocytes and animal models. [10][11][12][13][14] Stimulation of innate immune responses with TLR agonists may further 1 improve the immunotherapeutic effect of combination strategies against the hepadnaviral infection.…”

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

“…15,[21][22][23]25 The mechanism of reduced IFN-a production remains to be determined. The downregulation of TLR-9 26 and interference with the mTOR pathway 21 have been suggested as potential mechanisms, but these studies were performed on healthy donor pDCs exposed to HBV in vitro. It seems unlikely that this effect would be directly modulated by the virus or viral antigens because four studies found no correlation between the viral load in patients and reduced IFN-a production by pDCs.…”