Nonself RNA rewires IFN-β 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 the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-beta (IFN-beta) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-kappa B, consequently promoting IFNB transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3-NF-kappa B and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-kappa B induced, which converts IFN-beta-responding cells to IFN-beta-secreting cells.