Induction and function of IFNβ during viral and bacterial infection

Abstract

Since the discovery of the protein "interferon" over 50 years ago, IFNβ, an antiviral cytokine, has been well studied. In particular, the pathways inducing this cytokine during viral infection have been characterized, leading to the discovery of a multitude of pattern recognition receptors. IFNβ is also induced during bacterial infection, following recognition of bacterial ligands by the host viral and DNA sensors. However, the function of IFNβ during bacterial infection is variable and sometimes detrimental to the host. This review discusses the currently identified receptors and pathways engaged in IFNβ induction during infection, with emphasis on the role of IFNβ during bacterial infection.

Figure 1. Major pathways and sensors for IFNβ induction

A. TLRs: TLR4 and TLR3 can sense bacterial LPS and ds RNA respectively, and recruit the adaptor molecule TRIF. This leads to activation of NFκB and IRF3, mediated by the respective kinases. TLR7 and TLR9 recognize ssRNA and CpG DNA respectively in the lysosomal compartments and recruit adaptor molecule MyD88, leading to activation of NFκB and IRF7 activation. B. RLR/NLR: Recognition of viral dsRNA by MDA5 and RIG-I or ssRNA by NOD2, results in recruitment and activation of MAVS, and STING, leading to IRF3 phosphorylation. C. DNA sensors: This group is comprised of structurally unrelated proteins that recognize different forms of DNA. RNA polymerase III binds to polydAdT, and transcribes it to RNA, which in turn is recognized by RIG-I. IFI16 is major DNA sensor for longer DNA (>70 bp), and functions independent of MAVS. Bacterial metabolites di-cyc-AMP and di-cyc-GMP are recognized by unknown sensors. All DNA sensors require the adaptor molecule STING for downstream activation. LRRFIP1 recognize cytosolic dsRNA and DNA, and activates β-catenin. All pathways converge to binding of phosphorylated nuclear IRF3 and p65 to the IFNβ promoter resulting in IFNβ gene transcription.