Recent insights into the role of Toll-like receptors in viral infection

Abstract

Toll-like receptors (TLRs) have a central role in innate immunity as they detect conserved pathogen-associated molecular patterns (PAMPs) on a range of microbes, including viruses, leading to innate immune activation and orchestration of the adaptive immune response. To date, a large number of viruses have been shown to trigger innate immunity via TLRs, suggesting that these receptors are likely to be important in the outcome to viral infection. This suggestion is supported by the observation that many viruses have evolved mechanisms not only to evade the innate immune system, but also to subvert it for the benefit of the virus. In this review we will discuss earlier evidence, mainly from knock-out mice studies, implicating TLRs in the innate immune response to viruses, in light of more recent clinical data demonstrating that TLRs are important for anti-viral immunity in humans.

Fig. 1

Toll-like receptor (TLR) signalling and inhibition by viral proteins. Upon ligation of the TLRs with their respective ligands, TIR domain-containing adaptors are recruited to the receptors. MyD88 is the prototypical member of the group being utilized by all TLRs except TLR3, which utilizes TRIF only. TLR2 requires MAL along with MyD88 and TLR4 requires all four adapters, including TRAM, as a bridging adapter to TRIF. Adaptor recruitment leads to the activation of interleukin-1 receptor-associated kinase (IRAK4) and the phosphorylation of IRAK1. IRAK1 and IRAK2 signal to tumour necrosis factor (TNF) receptor-associated factor (TRAF)6, which leads to the activation of the transforming growth factor-β-activated kinase 1 (TAK)1-containing complex. This stimulates the kinase activity of the IκB kinase (IKK) complex and triggers the activation of NFκB, allowing its movement into the nucleus and the expression of proinflammatory cytokines. The pathway to IRF3 and IRF7 activation following TRIF stimulation from either TLR3 or TLR4 requires TRAF3 and the IKKε/TRAF family member-associated NF-κB activator-binding kinase 1 (TBK1) complex, resulting in type I IFN production. TLR7 and TLR9 activate the IRAK1/TRAF6 complex that stimulates IKKα phosphorylation and activation of IRF7, allowing the production of type I IFNs. A46R from the vaccinia virus associates with and inhibits all four adaptor proteins, MyD88, MAL, TRAM and TRIF. In contrast, A52R from vaccinia virus (VACV) binds to and inhibits IRAK2, while K7 inhibits DDX3, a component of the IKKε/TBK1 complex. The hepatitis C virus (HCV) protease NS3-4A cleaves and inactivates TRIF, while NS5A, also from HCV, sequesters MyD88.