Recent advances in understanding viral evasion of type I interferon - PubMed (original) (raw)

Review

Recent advances in understanding viral evasion of type I interferon

Kathryne E Taylor et al. Immunology. 2013 Mar.

Abstract

The type I interferon (IFN) system mediates a wide variety of antiviral effects and represents an important first barrier to virus infection. Consequently, viruses have developed an impressive diversity of tactics to circumvent IFN responses. Evasion strategies can involve preventing initial virus detection, via the disruption of the Toll-like receptors or the retinoic acid inducible gene I (RIG-I) -like receptors, or by avoiding the initial production of the ligands recognized by these receptors. An alternative approach is to preclude IFN production by disarming or degrading the transcription factors involved in the expression of IFN, such as interferon regulatory factor 3 (IRF3)/IRF7, nuclear factor-κB (NF-κB), or ATF-2/c-jun, or by inducing a general block on host cell transcription. Viruses also oppose IFN signalling, both by disturbing the type I IFN receptor and by impeding JAK/STAT signal transduction upon IFN receptor engagement. In addition, the global expression of IFN-stimulated genes (ISGs) can be obstructed via interference with epigenetic signalling, and specific ISGs can also be selectively targeted for inhibition. Finally, some viruses disrupt IFN responses by co-opting negative regulatory systems, whereas others use antiviral mechanisms to their own advantage. Here, we review recent developments in this field.

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Figures

Figure 1

Pathways to virus detection. Viral pathogen‐associated molecular patterns (PAMPs) are identified by various pattern recognition receptors (PRRs), such as the Toll‐like receptors (TLRs) and retinoic acid inducible gene I (RIG‐I)‐like receptors (RLRs). TLRs are found both at the plasma membrane and in endosomes, detect a variety of virus‐associated ligands, and signal through adaptors proteins Toll/interleukin‐1 receptor‐domain‐containing adapter‐inducing IFN‐β (TRIF), TRIF‐related adaptor molecule (TRAM), Mal and MyD88 to lead to the activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor‐κB (NF‐κB). RLRs retinoic acid inducible gene I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5), which are negatively regulated by LGP2, detect viral dsRNA, and signal through the adaptors mitochondrial antiviral signalling protein (MAVS) and STING to cause IRF3 and NF‐κB activation. Virtually every step in this process can be impeded by viral proteins.

Figure 2

Transcription factor activation to interferon (IFN) production. Detection of viral components by pattern recognition receptors (PRRs) leads to the activation of a variety of transcription factors. (a) Nuclear factor‐κB (NF‐κB) is held in an inactive cytoplasmic complex via interaction with its inhibitor, IκBα. Upon virus recognition, IκBα is phosphorylated in a process involving the regulatory component NEMO, leading to degradation of the inhibitor, freeing NF‐κB to translocate to the nucleus and bind the IFN promoter. (b) Upon virus detection, constitutively expressed interferon regulatory factor 3 (IRF3) is phosphorylated by the kinases TBK1 and IKKε, leading to its dimerization and nuclear translocation. (c) Although IRF7 is minimally expressed in most resting cell types, low level IFN production induces IRF7 expression, leading to its phosphorylation by TBK1/IKKε, heterodimerization with IRF3, nuclear translocation, and increased IFN expression. (d) The constitutively nuclear ATF2/cjun is phosphorylated upon virus detection by stress‐activated members of the mitogen‐activated protein (MAP) kinase superfamily, leading to the activation of the complex. Cooperative binding of NF‐κB, IRF3/IRF7 and ATF2/cjun to the IFN promoter leads to full expression of type I IFN genes. Each of these pathways is subject to inhibition by viruses.

Figure 3

Interferon (IFN) signalling to ISG expression. Secreted IFN binds to the cell‐surface receptor IFNAR, leading to the activation of kinases Tyk2 and Jak1, which phosphorylate and activate proteins signal transducer and activator of transcription 1 (STAT1) and STAT2. This results in the formation of a heterotrimeric complex containing interferon regulatory factor 9 (IRF9), known as IFN‐stimulated gene factor‐3 (ISGF3). Jak protein activation is negatively regulated by the IFN‐inducible proteins SOCS1 and SOCS3. Binding of ISGF3 to the promoters of ISGs leads to their transcriptional activation, and the collective actions of the hundreds of ISGs induced by IFN inhibit both virus replication and spread. Each aspect of this process can be disrupted by viral processes.

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Recent advances in understanding viral evasion of type I interferon - PubMed (original) (raw)