Decoding type I and III interferon signalling during viral infection

Abstract

Interferon (IFN)-mediated antiviral responses are central to host defence against viral infection. Despite the existence of at least 20 IFNs, there are only three known cell surface receptors. IFN signalling and viral evasion mechanisms form an immensely complex network that differs across species. In this Review, we begin by highlighting some of the advances that have been made towards understanding the complexity of differential IFN signalling inputs and outputs that contribute to antiviral defences. Next, we explore some of the ways viruses can interfere with, or circumvent, these defences. Lastly, we address the largely under-reviewed impact of IFN signalling on host tropism, and we offer perspectives on the future of research into IFN signalling complexity and viral evasion across species.

Fig. 1. Simplified schematic of type I and III IFN signalling cascades.

Within type I and III, there are multiple IFNs; within type II, there is only a single IFN. Each type has a distinct heterodimeric cell surface receptor: type I IFNs bind to the IFNAR receptor complex (composed of IFNAR1 and IFNAR2); type III IFNs bind to the IFNLR receptor complex (composed of INFLR1 and IL-10Rβ). Binding of an IFN to either receptor complex results in cross-phosphorylation of JAK1 and TYK2 on the cytoplasmic domains of the receptor subunits. This triggers phosphorylation of STAT1 and STAT2. Following phosphorylation, these STATs form various complexes that translocate into the nucleus, where they bind IFN-stimulated response elements (ISREs) or gamma-activated sequences (GASs) on the promoters of ISGs. Binding to these promoter elements results in the transcription of hundreds of genes involved in antiviral response, including ISGs, IFNs, IRFs and STATs. P, phosphate; OASs, oligoadenylate synthases; GBPs, guanylate-binding proteins; NOS2, nitric oxide synthase 2; IFITMs, IFN-induced transmembrane proteins; TRIMs, tripartate motif proteins.

Fig. 2. Factors that influence the decoding of IFN signalling inputs.

Various factors influence the decoding of IFN signalling inputs. (1) Receptor-binding affinities: each type I IFN binds to the IFNAR complex with varied affinities. These affinities correspond with differences in certain signalling outputs. As of yet, the binding affinities of type III IFNs have not been calculated. (2) Negative regulation: gene products induced by IFN signalling have the ability to negatively regulate the cascade at various stages; for example, SOCS1 and SOCS3, which interfere with TYK2 and JAK1, and STAT3, which can suppress STAT1 monomers, preventing homodimerization. (3) Positive regulation and signal amplification: factors such as STAT1, IRF9 and IRF7 can enhance IFN signal transduction. This leads to prolonged expression and secretion of antiviral cytokines and IFNs that can adjust the IFN cascade or lock the cell into an autocrine signalling loop. (4) Receptor expression and assembly: levels of receptor expression at the cell membrane contribute to differential signalling abilities of IFNs across cell types. Further, alterations to receptor assembly, such as the kinetics of subunit endocytosis, can influence signalling. (5) Biomolecular condensation: formation of cellular compartments caused by phase separation of biomolecules appears to influence various stages of IFN signalling; for example, phase separation of cGAS facilitates sensing of viral genetic material to induce expression of IFNs. Kd, dissociation constant.

Fig. 3. Hypothetical models of different transcriptional outputs in response to viral infection.

During viral infection, differential IFN signalling inputs may manifest as differences in the magnitude of induced ISGs (a), kinetics of ISG transcription and degradation (b) or composition of ISGs expressed in the transcriptional profile (c). These variations, or a combination thereof, appear to play a significant role in cell-, virus- and species-specific antiviral responses.

Fig. 4. Examples of RNA viral antagonism upstream of IFN induction.

After entering a cell, viral genetic material may be recognized by one or more of the host’s PRRs. These include RLRs, Toll-like receptors (TLRs) and cGAS. Recognition by one or more of these PRRs triggers a signalling cascade that culminates in the transcription and subsequent generation of IFNs. Different viruses have evolved to antagonize these pathways at virtually all stages, indicated by blunt end arrows. Solid arrows indicate direct pathway connections. Dashed arrows indicate signal cascade components present in vivo but not shown for space concerns. Asterisks indicate viral antagonism by an unknown mechanism. See Table 1 for specific mechanisms at each stage. LGP2, laboratory of genetics and physiology protein 2; MDA-5, melanoma differentiation-associated protein 5; TRIF, TIR domain-containing adapter-inducing IFN-β; IKK-ε, IκB kinase-ε; HAV, hepatitis A virus; hCoV-NL63, human coronavirus NL63; PEDV, porcine epidemic diarrhea virus; GTOV, Guanarito virus; JUNV, Junin virus; MAVC, Machupo virus; SABV, Sabia virus; BDV, Borna disease virus; SFTSV, severe fever with thrombocytopenia syndrome virus; JEV, Japanese encephalitis virus; ANDV, Andes virus; SNV, Sin Nombre virus.

Fig. 5. Examples of RNA viral antagonism downstream of IFN induction.

Following IFN binding to their receptor in an autocrine or paracrine manner, a signalling cascade takes place that results in the transcription and expression of ISGs. These ISGs are critical for establishing an antiviral state in the host and bystander cells. Different viruses have evolved to antagonize this pathway at virtually all stages, indicated by blunt end arrows. Solid arrows indicate direct pathway connections. The asterisk indicates viral antagonism by an unknown mechanism. See Table 2 for specific mechanisms at each stage.