Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection - PubMed
Review
Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection
Ejuan Zhang et al. Med Microbiol Immunol. 2015 Feb.
Abstract
The role of adaptive immune responses in the control of hepatitis B virus (HBV) infection is well accepted. The contribution of innate immune responses to the viral control is recognized but yet not fully understood. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms including the intracellular antiviral pathways and the production of antiviral effectors like interferons (IFNs) and pro-inflammatory cytokines. Activation of the TLR3 pathway and the production of IFN-β represent one of the major mechanisms leading to the suppression of HBV replication in the liver, as shown in different in vitro and in vivo models. TLR4 signaling and TLR2 signaling result in the activation of intracellular pathways including MAPK and PI-3 K/Akt in hepatocytes and reduce HBV replication in an IFN-independent manner. HBV is able to counteract the actions of TLR3 and TLR2/4 through downregulation of TLR expression and attenuation of the cellular signaling pathways. Thus, TLR ligands are promising candidates as immunomodulators and therapeutics for the treatment of chronic HBV infection. Specific antiviral treatment against HBV could recover the TLR functions in chronic HBV infection and increase the effectiveness of therapeutic approaches based on TLR activation.
Figures

TLR signaling. Upon the activation of TLRs by their respective ligands, the adaptor molecules MYD88, TIRAP, TRIF, and TRAM are recruited and further activate the kinases TAK1, MAPKs, TRAF3, TBK1, and IKKs, resulting in nuclear translocation of transcriptions factors AP-1, NF-κB, IRF3, or IRF7, and subsequent transcription of IFNs and pro-inflammatory cytokines

Interaction of HBV and TLR3. TLR3 activation in hepatic NPCs leads to the production of IFN-β and subsequently the upregulation of ISGs in hepatocytes. Antiviral ISGs like MxA and IFIT1/2 inhibit HBV replication at the transcriptional and posttranscriptional steps. HBV virions and proteins are able to suppress TLR3 signaling and block IFN-β production. HBV polymerase could interfere with IRF3 action and block the nuclear translocation of Stat1/2

Interaction of HBV and TLR2/4. TLR2/4 activation in hepatocytes inhibits HBV replication in an IFN-independent manner but requires the participation of intracellular signaling pathways like MAPK pathway. TLR4 stimulation in KCs leads to the production of IFN-β and an unknown antiviral effector which inhibits HBV replication in hepatocytes. HBV downregulates TLR2/4 expression during chronic HBV infection. HBsAg and HBeAg are able to block TLR2 signaling at different steps, preventing the production of pro-inflammatory cytokines
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