Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice

Abstract

Hepatitis B virus (HBV) infection isCurrently, only interferon (IFN)-␣ and nucleoside or nucleotide analogues have been shown to be effective in suppressing HBV replication and in inducing clinical remission of liver disease. 2 However, increasing evidence suggests that immune mediators such as Toll-like receptor (TLR) ligands could be used successfully as therapeutic agents in HBV 3 or other viral infections. [4][5][6] TLRs play a crucial role in early host defense by recognizing so-called pathogen-associated molecular patterns that are essential for the survival of the microorganism but are not present in eukaryotes. 7 To date, 13 mammalian TLRs have been identified (10 in humans and 13 in mice), each containing a unique extracellular domain and a conserved cytoplasmic Toll/interleukin (IL)-1 receptor domain. 8 After ligand binding, the cytoplasmic Toll/IL-1 receptor domain of TLRs associates with intracellular adapters and activates downstream signaling molecules, including the transcription factors nuclear factor B, interferon regulatory factor-1, interferon regulatory factor-7, and mitogen-activated protein kinases, which lead to the activation of type I IFNs, proinflammatory cytokines, or costimulatory molecules. 9 Five adapter proteins

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

“…Regardless of the fact that TLR-mediated innate immunity is not or is only weakly activated by HBV infection, experimental activation of the TLR system in hepatic cells and in the liver could suppress HBV replication in vitro and in vivo [10][11][12][13][14] ( Figure 1). Early experiments in HBV transgenic mice demonstrated the ability of TLR3 ligand poly(I:C) to induce IFN-adependent suppression of HBV replication.…”

“…Hepatic NPCs, including KCs and liver sinusoidal endothelial cells (LSECs), play a key role in the TLR-mediated inhibition of HBV. 11 The supernatants of TLR3-or TLR4-activated KCs and TLR3-activated LSECs efficiently inhibited HBV replication in an immortalized murine hepatocyte cell line derived from HBV transgenic mice (HBVMet). The antiviral effect of TLR3 was largely mediated by IFNb, whereas the factor for the TLR4 effect remained undefined.…”

“…The antiviral effect of TLR3 was largely mediated by IFNb, whereas the factor for the TLR4 effect remained undefined. 11 Myeloid dendritic cells (DCs) respond to a broad range of TLR ligands, including those for TLR1/2, -3, -4, -7 and -9, to produce antiviral cytokines, which in turn inhibit HBV replication in HBV-Met cells. 11 Thus, TLR activation in hepatic NPCs and extra-hepatic DCs could significantly reduce HBV replication through secretion of type I IFNs or other antiviral cytokines.…”

Toll-like receptor 3 gene polymorphisms are not associated with the risk of hepatitis B and hepatitis C virus infection

“…TLR3 activation effi ciently suppresses HBV replication through the stimulation of IFN-β in murine liver cells (17) . However, HBV polymerase inhibits IFN-β promoter region activity, thus blocking both IFN-β expression and TLR3-mediated antiviral activity (18) .…”

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

“…25 Unlike most viruses, HBV infection does not induce the expression of antiviral genes in chimpanzees; thus, the virus spreads throughout the liver. 26 Recently, several groups demonstrated that forced induction of type I IFNs by the overexpression of TLR or RLR signaling components inhibits HBV replication in the following experimental systems: in vivo, 27 in mice non-parenchymal cells 28 and in HepG2 and Huh7 cells. 29 The Wu group also determined that Toll-like receptors mediate IRF3 and IFN-b activation and can be inhibited by a high level of HBV replication in HBV-Met cells.…”