Antagonism of interferon signaling by fibroblast growth factors promotes viral replication

Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross‐talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferon‐stimulated genes (ISG) and proteins in vitro and in vivo . Conversely, FGF7 or FGF10 treatment of keratinocytes suppressed ISG expression under homeostatic conditions and in response to IFN or poly(I:C) treatment. FGF‐mediated ISG suppression was independent of IFN receptors, occurred at the transcriptional level, and required FGF receptor kinase and proteasomal activity. It is not restricted to keratinocytes and functionally relevant, since FGFs promoted the replication of herpes simplex virus I (HSV‐1), lymphocytic choriomeningitis virus, and Zika virus. Most importantly, inhibition of FGFR signaling blocked HSV‐1 replication in cultured human keratinocytes and in mice. These results suggest the use of FGFR kinase inhibitors for the treatment of viral infections. Synopsis The study demonstrates that fibroblast growth factors suppress the cellular interferon response and thereby promote viral replication. Inhibition of FGF signaling has the opposite effect, suggesting the use of FGF receptor inhibitors as an antiviral defense strategy. FGF signaling suppresses the basal expression of interferon response genes in keratinocytes and intestinal epithelial cells. The effect of FGF signaling on the interferon response is mediated via the FGF receptor kinase and occurs at the transcriptional level. FGF signaling suppresses the interferon response upon treatment of cells with interferons, interferon‐inducers, and upon viral infection. FGF signaling promotes replication of Herpes simplex virus I, lymphocytic choriomeningitis virus and Zika virus in keratinocytes. FGF receptor inhibition has strong antiviral activities in keratinocytes. Graphical Abstract The study demonstrates that fibroblast growth factors suppress the cellular interferon response and thereby promote viral replication. Inhibition of FGF signaling has the opposite effect, suggesting the use of FGF receptor inhibitors as an antiviral defense strategy.