S-6 Novel interferon and interferon-independent signaling pathways

Primary cells such as fibroblasts rapidly respond to virus infection and extracellular dsRNA by making type I interferon, a pleiotropic cytokine with potent antiviral activity. The prototypic signaling pathways include recognition by members of the Toll-like receptor (TLR) and Retinoic acid-like receptor (RLR) families and subsequent activation of the transcription factor interferon regulatory factor 3 (IRF3). Production of IFNβ subsequently leads to induction of IRF7 and activation of IFN-alpha species, along with a myriad of interferon stimulated genes (ISGs). We previously discovered that virus particle entry induces a subset of ISGs in the absence of IFN production. Membrane perturbation was found to be sufficient for this IFN-independent antiviral response. Recent data implicates both calcium signaling and reactive oxygen species induction in this antiviral response. Unlike the IFN-independent antiviral response, which is completely dependent on IRF3, the production of type I IFN in response to long dsRNA, consistent with the size of many viral dsRNA species, is completely independent of IRF3 and can occur in the absence of both IRF3 and IRF7. Preliminary data suggests that in this context, IRF9 is essential for the initial production of IFNβ upon stimulation of fibroblasts with dsRNA.