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

Abstract

AbstractViral RNA-activated transcription factors IRF3 and NF-κB trigger synthesis of interferons and interleukins. In non-infected bystander cells, the innate immune response is reinforced by secreted interferon β (IFNβ), which induces the expression of interferon-activated genes (ISGs) through activation of STAT1/2. 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 IFNβ receptor, IFNAR. We demonstrate that two ISGs, RNase L and PKR, not only hinder replenishment of IFNAR, but also suppress negative regulators of IRF3 and NF-κB, consequently promoting their transcriptional activity. We incorporated these findings into a comprehensive mathematical model of innate immunity. By coupling signaling through the IRF3/NF-κB and the STAT1/2 pathways with activity of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from STAT1/2-induced to IRF3/NF-κB-induced, transforming IFNβ-responding cells into IFNβ-secreting cells. Using an ample set of experiments on wild-type and knock-out A549 cell lines for fitting the model, we managed to achieve parameter identifiability.