Viral recognition and the antiviral interferon response

Abstract

Interferons (IFNs) are antiviral cytokines that play a key role in the innate immune response to viral infections. In response to viral stimuli, cells produce and release interferons, which then act on neighboring cells to induce the transcription of hundreds of genes. Many of these gene products either combat the viral infection directly, e.g., by interfering with viral replication, or help shape the following immune response. Here, we review how viral recognition leads to the production of different types of IFNs and how this production differs in spatial and temporal manners. We then continue to describe how these IFNs play different roles in the ensuing immune response depending on when and where they are produced or act during an infection.

Keywords: Interferon; Interferon Regulatory Factor 3 (IRF3); Interferon induction; viral recognition.

Figure 1. Recognition of viral infection by pattern recognition receptors leads to interferon production

Viral recognition leads to interferon induction via three principal pathways that are characterized by the adaptor proteins used to connect the upstream pattern recognition receptors with the downstream signaling machinery. Signaling via those pathways is orchestrated by the adaptor proteins STING, MAVS and either TRIF or MyD88. All the three pathways activate the kinase TBK1, which in turn phosphorylates the transcription factors IRF3 and IRF7. Notably, IRF7 is constitutively expressed in pDCs but needs to be induced by IFN signaling in other cells. In addition, these pathways also activate the NF–κB family of transcription factors, yet the molecular mechanism behind this activation remains poorly characterized.

Figure 2. The activation mechanism of IRF3

IRF3 docks to the phosphorylated form of the adaptor proteins illustrated here by STING. Once docked at the adaptor proteins, TBK1 phosphorylates IRF3 at key serine residues where residue 386 is particularly critical for IRF3 activation. Upon phosphorylation, IRF3 dimerizes and forms the transcriptionally active dimer, which then translocates to the nucleus where it drives transcription of IFNs and certain antiviral genes. The available data suggest that IRF7 is activated through a similar mechanism.

Figure 3. Interferon signaling leads to the establishment of an antiviral state in uninfected cells

Recognition of a viral infection in infected cells leads to production of IFN‐β and IFN‐λ, whereas recognition of viruses by pDCs leads to production of large amount of IFN‐α. The IFNs signal through their respective receptor complexes to induce the expression of ISGs in uninfected cells and thereby establish an antiviral state.