Toll-like receptors in antiviral innate immunity

Abstract

Toll-like receptors (TLRs) are fundamental sensor molecules of the host innate immune system, which detect conserved molecular signatures of a wide range of microbial pathogens and initiate innate immune responses via distinct signaling pathways. Various TLRs are implicated in the early interplay of host cells with invading viruses, which regulates viral replication and/or host responses, ultimately impacting on viral pathogenesis. To survive the host innate defense mechanisms, many viruses have developed strategies to evade or counteract signaling through the TLR pathways, creating an advantageous environment for their propagation. Here we review the current knowledge of the roles TLRs play in antiviral innate immune responses, discuss examples of TLR-mediated viral recognition, and describe strategies used by viruses to antagonize the host antiviral innate immune responses.

Keywords: cytokine; interferon; interferon regulatory factor; nuclear factor-kappa B; virus.

Graphical abstract

Fig. 1

Recognition of viral PAMPs such as viral proteins, dsRNA, ssRNA, and CpG DNA, initiates an antiviral innate immune response mediated by TLRs. TLR2 and TLR4 are present on the cell surface and recognize viral proteins. TLR3, TLR7, TLR8, and TLR9 are intracellular viral nucleic-acid-sensing TLRs that are localized in endosomes. Viral dsRNA, ssRNA, and unmethylated CpG DNA are recognized by TLR3, TLR7/TLR8, and TLR9, respectively. Upon ligand recognition, TLR2 along with TLR6 or TLR1 and TLR4 recruits an additional adaptor protein, MAL, to link the TIR domain to MyD88. All TLRs except TLR3 recruit MyD88. TLR4 also recruits the adapter protein TRIF, as does TLR3. To activate the TRIF-dependent pathway, TLR4 requires the bridging adaptor TRAM and its trafficking into endosomes. The MyD88-dependent and TRIF-dependent signaling complexes through a cascade of signaling events leading to the activation of several transcription factors including NF-κB, IRF3, and IRF7. NF-κB transcriptionally regulates the expression of inflammatory cytokines and chemokines while IRF3 and IRF7 control the transcription of type I and type III IFN genes. Whereas TLR2 signaling only results in NF-κB activation in most cell types, TLR2 can traffic to endosomes in inflammatory monocytes upon engagement of specific viral ligands such as vaccinia virus or MCMV where it results in IRF3/IRF7 activation and type I IFN induction (not depicted).