Non-self RNA rewires IFNβ signaling: A mathematical model of the innate immune response

Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which through activation of STAT1/2 in bystander cells induce the expression of IFN-stimulated genes (ISGs). The complex system-level mechanisms of IFN signaling are however not well understood. Here, we show that in cells transfected with an analog of viral RNA, poly(I:C), transcriptional activity of STAT1/2 is terminated due to depletion of the interferon {beta} (IFN{beta}) receptor, IFNAR. Two ISGs, RNase L and PKR, not only hinder replenishment of IFNAR, but also suppress negative regulators of IRF3 and NF-{kappa}B, consequently promoting IFN{beta} transcription. We incorporated these findings into a comprehensive mathematical model of innate immunity. By coupling signaling through the IRF3/NF-{kappa}B and STAT1/2 pathways with the activity of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from STAT1/2-induced to IRF3/NF-{kappa}B-induced, turning IFN{beta}-responding cells to IFN{beta}-secreting cells. One-sentence summaryA computational model explains how non-self RNA turns cells from IFN{beta}- responders to IFN{beta}-producers.