Size matters: Mathematical modelling of the type‐1 interferon induction

Retinoic acid-inducible gene I (RIG-I) is a cytoplasmic innate immune receptor for viral RNA. RIG-I detects viral RNA and triggers an antiviral response by activating the type I interferon (IFN) pathway. While it is known that a 5′-triphosphate end, as well as double-strandedness of RNA constitute molecular patterns recognised by RIG-I, the underlying mechanism is less well established. Recent experiments show a RNA length-dependent activation of the IFN response, with long dsRNA evoking a larger immune response than short RNA at non-saturating concentrations. We developed a mathematical model of viral RNA recognition by RIG-I, as well as the activation of downstream players in the pathway. Our model is able to explain quantitative activation curves of RIG-I enzymatic activity, as well as the cellular response of IFN transcription depending on RNA length and concentration. Furthermore, it is consistent with additional data from structural microscopy and size exclusion experiments. Our model predicts an important role of cooperative binding in RNA recongnition, showing how RIG-I has evolved to sensitively detect cellular infections by RNA viruses such as influenza. The cooperative binding of RIG-I along the length of RNA molecules ensures a large immune response even at low copy numbers of viral RNA genomes.