The Roles of Type I Interferon in Bacterial Infection

Abstract

Type I interferons (IFNs) are pleiotropic cytokines well recognized for their role in the induction of a potent antiviral gene program essential for host defense against viruses. They also modulate innate and adaptive immune responses. However, the role of type I IFNs in host defense against bacterial infections is enigmatic. Depending on the bacterium, they exert seemingly opposite and capricious functions. In this review, we summarize the effect of type I IFNs on specific bacterial infections and highlight the effector mechanisms regulated by type I IFNs in an attempt to elucidate new avenues to understanding their role.

Figure 1. Signaling pathways leading to the induction of type I IFNs

Recognition of components derived from bacteria occurs at the membrane and in the cytosol. Ligand binding of TLRs recruits the signaling adapter molecule MyD88 to TLR2/7/8/9/13 leading to activation of IRF kinases IRAK and IKKα. TLR4 recruits the adaptor TRIF and together they activate the IRF kinases TBK1 and IKKε. Engagement of cytosolic sensors leads to the recruitment of the signaling adapter molecule MAVS to the RLRs (RIG-I and MDA-5), STING to the DNA sensors (cGAS, DDX41 and IFI16), and RIP2 to the NLRs (NOD1 and NOD2). Like TRIF, cytosolic signaling adapters all activate TBK1 and IKKε. IRF kinases activate IRFs by phosphorylation dependent dimerization, allowing them to translocate into nucleus and drive type I FN expression.

Figure 2. Type I IFNs induce ISGs expression through JAK/STAT signaling

Binding of type I IFNs to the IFNAR1-IFNAR2 heterodimer activates Janus kinases, JAK1 and TYK2, to phosphorylate STAT transcription factors. Dimerization of activated STAT1 and STAT2 further recruits IRF9 and forms the ISGF3 complex, that promotes expression of genes containing an ISRE sequence in their promoter. Homodimerization of activated STAT1, drives the expression of genes containing a γ-activated sequence (GAS) in their promoter.

Figure 3. Effector mechanisms mediated by type I IFNs during bacterial infection

Autocrine and paracrine signaling of type I IFNs suppress type II IFN signaling, proinflammatory responses and production of antimicrobial peptides to contribute to overall detrimental host outcomes. Modulation of metabolism by type I IFNs also exerts negative effects by either suppressing sterol biosynthesis and PGE2 or by upregulating CH25H, but may also promote host defense by inducing expression of IRG1. Tissue integrity is strengthened by type I IFNs through the induction of tight junction (TJs) proteins, claudins and occludins, yet suppressive effects on ILC2s and amphiregulin are also observed. See text for details.