Toll-like receptor 3 in hepatitis B and C: a determinant of infection.

Abstract

Toll-like receptor 3 (TLR3) is a key component of the innate immune system that recognizes viral double-stranded RNA (dsRNA) as well as endogenous RNA released from necrotic cells. Unlike other TLRs, TLR3 signals exclusively through the TIR-domain-containing adaptor inducing interferon-β (TRIF). This activation triggers downstream cascades that culminate in the translocation of IRF3 and NF-κB, inducing type I and type III interferons (IFNs) alongside interferon-stimulated genes (ISGs) and pro-inflammatory cytokines. These responses are essential for shaping antiviral immunity in hepatitis virus infections. In hepatitis B virus (HBV) infection, exogenous stimulation of TLR3 using synthetic agonists such as polyriboinosinic: polyribocytidylic acid [poly(I:C)] suppresses viral replication in experimental models and promotes interferon-dependent viral clearance, underscoring its therapeutic potential. In hepatitis C virus (HCV) infection, TLR3-mediated antiviral defenses are directly antagonized, most notably through cleavage or downregulation of TRIF by viral proteins, thereby impairing IFN induction and facilitating viral persistence. Furthermore, human genetic studies reveal that TLR3 polymorphisms, such as the non-synonymous rs3775290 (1377 C > T), are associated with differential susceptibility, chronicity, and progression of HBV and HCV infections. Collectively, the evidence highlights TLR3 as a central determinant of host-virus interactions in hepatitis, influencing viral clearance, persistence, and clinical outcomes, and as a promising target for novel therapeutic strategies. This review provides an updated overview of TLR3 expression and genetic variants in relation to HBV and HCV infection outcomes.