Viral evasion and subversion of pattern-recognition receptor signalling

Key Points

• Viruses are detected by different classes of pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and cytoplasmic DNA receptors. This leads to the activation of downstream signalling pathways that culminate in the activation of transcription factors and the production of type I interferons (IFNs).

• Investigating how viruses interact with PRR signalling pathways provides insights into how the pathways function, which host proteins are involved and how the pathways might be manipulated therapeutically.

• TLRs and RLRs are inhibited in various ways by viruses: the main viral mechanism for inhibiting TLR signalling to be identified so far is the disabling of the TIR (TLR/interleukin-1 receptor)-domain-containing adaptor proteins, which are required for the activation of transcription factors. Although described only recently, RLRs have already been shown to be crucial for sensing viruses. Consequently, many viral strategies that are targeted against them have already been identified.

• All PRR signalling pathways converge with the activation of IκB kinase (IKK) family members. So, direct inhibition of IKKs is an efficient viral strategy to disable multiple PRR pathways and it is used by many viruses.

• The transcription factors that control IFN induction, IFN-regulatory factor 3 (IRF3), IRF7 and nuclear factor-κB, are also directly antagonized by viruses. IRF3 in particular is subject to virus-induced degradation.

• Viruses also actively subvert TLRs to manipulate the host cytokine environment for their own benefit.

Abstract

This Review highlights how understanding the mechanisms by which viruses evade and subvert host signalling by pattern-recognition receptors has provided insights into the function of these signalling pathways, the host proteins that are involved and ways in which the pathways might be manipulated therapeutically.

Abstract

The expression of pattern-recognition receptors (PRRs) by immune and tissue cells provides the host with the ability to detect and respond to infection by viruses and other microorganisms. Significant progress has been made from studying this area, including the identification of PRRs, such as Toll-like receptors and RIG-I-like receptors, and the description of the molecular basis of their signalling pathways, which lead to the production of interferons and other cytokines. In parallel, common mechanisms used by viruses to evade PRR-mediated responses or to actively subvert these pathways for their own benefit are emerging. Accumulating evidence on how viral infection and PRR signalling pathways intersect is providing further insights into the function of the pathways involved, their constituent proteins and ways in which they could be manipulated therapeutically.