Figure 6.

Probable signaling in the mechanism induced by TLRs, IFNRs, RIG-I, and STING in the control of the viral infection and how the virus interferes with them (marked with a red X). The stimulus of TLRs can induce a response to eliminate HBV. HBV presence leads to downregulation of the expression of TLRs (observed in PBMCs; indicated with red arrows) and/or interfere with its signaling (blocking the MyD88-IRAK4 axis, suppressing IRF3 activation, inhibiting the expression and nuclear translocation of IFR7). The virus can also inhibit RIG-I/MDA5-mediated response and STING-stimulated IRF3 activation; blocks: the activation of interferon IRF3 and IRF7, TBK1/IKKε activation, STING-stimulated IRF3 activation and, down-regulate the expression of MAVS. The presence of the virus can also interfere with IFN receptors signaling by avoiding nuclear translocations of STAT1/2 and IFN-α-induced STAT activation. Abbreviations: HBV, hepatitis B virus; NTCP, Na+-Taurocholate co-transporting polypeptide; TLR4, Toll-like receptor 4; TLR7/9, Toll-like receptor 7 and 9; MyD88, Myeloid differentiation primary response 88; TIRAP, TIR domain-containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRAF, TNF Receptor Associated Factor; NAP1, NF-kB–activating kinase-associated protein 1; IRF, interferon regulatory factor; TBK1, TANK binding kinase 1; IKKε, IκB kinase-ε; STING, stimulator of interferon genes; STAT, signal transducers and activators of transcription; IRF9, IFN regulatory factor 9; ISG, interferon stimulated genes; ISGF3, ISG factor 3; SOC; IFN-induced suppressor of cytokine signaling; GAS gamma IFN activated sequence (GAS) gamma IFN activated sequence GAS; MAVS, mitochondrial antiviral signaling; cGAMP, cyclic-GMP-AMP; cGAS, cyclic-GMP-AMP synthase; GAF, IFN-γ activated factor.