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Review
. 2008 Dec;8(12):911-22.
doi: 10.1038/nri2436.

Viral evasion and subversion of pattern-recognition receptor signalling

Andrew G Bowie  1 , Leonie Unterholzner
Affiliations
Review

Viral evasion and subversion of pattern-recognition receptor signalling

Andrew G Bowie et al. Nat Rev Immunol. 2008 Dec.

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.

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Figures

Figure 1
Figure 1. Activation of the interferon response triggered by the detection of viral pathogen-associated molecular patterns.
All of the pattern-recognition receptors (PRRs) initiate signalling pathways that converge at the activation of the transcription factors interferon (IFN)-regulatory factor 3 (IRF3), IRF7 and/or nuclear factor-κB (NFκB); this leads to the expression of IFNβ. IFNβ then initiates an antiviral effector programme in the infected cell and neighbouring cells, which involves the expression of numerous IFN-stimulated genes (ISGs). Some of the ISGs shown here, such as RIG-I (retinoic-acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5), DAI (DNA-dependent activator of IRFs), some microRNAs and the TRIM (tripartite motif-containing) family of proteins, are involved in the amplification and regulation of the IFN response. Other ISGs shown here, such as 2′5′-oligoadenylate synthetase (OAS) and ribonuclease L (RNaseL), IFN-inducible dsRNA-dependent protein kinase (PKR), myxovirus resistance (Mx) protein, adenosine deaminase RNA-specific (ADAR) and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3 (APOBEC3), are involved in antiviral mechanisms that interfere with the life cycle of individual viruses . OAS and PKR are further activated by double-stranded RNA (dsRNA). IFNAR1, interferon-α receptor; IPS1, IFNB-promoter stimulator 1; ISG15, IFN-stimulated protein of 15 kDa; MD2, myeloid differentiation protein 2; PPP, 5′ triphosphate; ssRNA, single-stranded RNA; STAT, signal transducer and activator of transcription; TLR, Toll-like receptor.
Figure 2
Figure 2. Viral evasion of Toll-like receptor signalling.
Following activation, Toll-like receptors (TLRs) recruit the adaptor proteins myeloid differentiation primary-response gene 88 (MyD88), TIR-domain-containing adaptor protein inducing IFNβ (TRIF), MyD88-adaptor-like (MAL) and TRIF-related adaptor protein (TRAM), as indicated. These then initiate signalling cascades involving IL-1R-associated kinase (IRAK) and TNFR-associated factor (TRAF) proteins, which finally converge at the activation of the IκB kinase (IKK) family members IKKα, IKKβ, IKKɛ and TBK1 (TANK-binding kinase 1). The vaccinia virus (VACV) protein A46R sequesters all these adaptor proteins, whereas the hepatitis C virus (HCV) protein NS5A selectively binds MyD88 and the HCV NS3–4A protease cleaves TRIF. Human T-cell leukaemia virus type 1 (HTLV-1) protein p30 acts even further upstream by reducing the expression of TLR4. VACV A52R binds to and inhibits IRAK2, thereby affecting several TLR pathways that lead to nuclear factor-κB (NFκB) activation. dsRNA, double-stranded RNA; IFN, interferon; IL-1R, interleukin-1 receptor; IRF, IFN-regulatory factor; IκB, inhibitor of NFκB; MD2, myeloid differentiation protein 2; ssRNA, single-stranded RNA; RIP1, receptor-interacting protein 1; TAB, TAK1-binding protein; TAK1, transforming-growth-factor-β-activated kinase 1; TANK, TRAF-family-member-associated NFκB activator; TIR, TLR/IL-1R; TNFR, tumour-necrosis factor receptor; TRADD, TNFR-associated via death domain.
Figure 3
Figure 3. Viral evasion of retinoic-acid-inducible-gene-I-like receptor signalling.
RIG-I (retinoic-acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5), termed RIG-I-like receptors (RLRs), are activated by cytoplasmic RNA during viral infection. Both signal using IFNB-promoter stimulator 1 (IPS1), which is tethered to the mitochondrial membrane. When IPS1 is engaged by RLRs, it recruits downstream signalling complexes that lead to the activation of the IFN-regulatory factors (IRFs) and nuclear factor-κB (NFκB). In addition, signalling through RIG-I requires the adaptor STING (stimulator of IFN genes), which resides in the endoplasmic reticulum (ER). RLR signalling is inhibited by viral proteins that either bind RIG-I, MDA5 or IPS1 directly or cause their degradation. The IκB kinase (IKK) family members are also a common target for viral proteins. DDX3, DEAD-box protein 3; dsRNA, double-stranded RNA; FADD, FAS-associated via death domain; HAV, hepatitis A virus; HCV, hepatitis C virus; IFN, interferon; IκB, inhibitor of NFκB; LGP2, laboratory of genetics and physiology 2; NAP1, NFκB-activating kinase-associated protein 1; NS1, nonstructural protein 1; PPP, 5′ triphosphate; RIP1, receptor-interacting protein 1; SINTBAD, similar to NAP1 TBK1 adaptor; ssRNA, single-stranded RNA; TANK, TRAF-family-member-associated NFκB activator; TBK1, TANK-binding kinase 1; TNFR, tumour-necrosis factor receptor; TRADD, TNFR-associated via death domain; TRAF, TNFR-associated factor; TRIM25, tripartite motif-containing 25; ub, ubiquitin; VACV, vaccinia virus.
Figure 4
Figure 4. Inhibition of interferon-regulatory factor 3 (IRF3) and IRF7 by viral proteins.
IRF3 and IRF7 are activated by phosphorylation, they then homodimerize and translocate to the nucleus, where they interact with their co-activators CREB-binding protein (CBP) and p300 and induce the expression of genes such as interferon-α (IFNA) and IFNB. Viruses inhibit IRFs by inducing their degradation, sequestering them or competing with them for binding to promoter sequences. AP1, activator protein 1; ATF2, activating transcription factor 2; BHV, bovine herpesvirus; CREB, cyclic-AMP-responsive-element-binding protein; CSFV, classical swine fever virus; HHV, human herpesvirus; HSV, herpes simplex virus; ICP0, infected cell protein 0; NDV, Newcastle disease virus; NFκB, nuclear factor-κB; NSP1, non-structural protein 1; KSHV, Kaposi's sarcoma-associated herpesvirus.
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