Antagonism of interferon signaling by fibroblast growth factors promotes viral replication

Abstract

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.

Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis

“…The molecular mechanism underlying how club cell-driven FGF9 overexpression might promote a type I IFN signature upon infection remains unclear. Within the current literature, FGFs commonly inhibit or suppress the functions of IFNs in both disease and development contexts [ 38 – 40 ]. Recently, multiple studies have demonstrated that FGF-driven antagonism of IFN signaling can promote viral pathogenesis.…”

“…Recently, multiple studies have demonstrated that FGF-driven antagonism of IFN signaling can promote viral pathogenesis. For example, FGF7 treatment of keratinocytes enhanced herpes simplex virus-1, lymphochoriomeningitis virus, and Zika virus infection by inhibiting ISG expression [ 40 ]. Additionally, Zika virus infection of human fetal astrocytes elevated expression of FGF2, which suppressed IFN signaling and facilitated Zika virus infection and spread [ 41 ].…”

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

“…The demonstration that EGF and FGF2 help retain FOXG1 nuclear localization following ZIKV infection, and that ZIKV induces FGF2 expression supports the combinatorial or dose-dependent role of GFs in forebrain shaping, the pathophysiological relevance of FGF2, and suggests a further role of GFs in ZIKV spread. In this context, recent reports also show that ZIKV induces FGF2 expression and FGF2 facilitates virus replication and cell-to-cell spread ( Limonta et al., 2019 ); moreover, in ZIKV-infected pregnant women, blood concentration of FGF2 correlates with the severity of the affected fetuses ( Kam et al., 2017 ) and, finally, FGF2 receptor inhibitors have been suggested as a promising approach for antiviral therapies ( Carlin, 2022 ; Langford et al., 2005 ; Maddaluno et al., 2020 ).…”

Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis

“…Recently, multiple studies have demonstrated that FGF-driven antagonism of IFN signaling can promote viral pathogenesis. For example, FGF7 treatment of keratinocytes enhanced herpes simplex virus-1, lymphochoriomeningitis virus, and Zika virus infection by inhibiting ISG expression 41 . Additionally, Zika virus infection of human fetal astrocytes elevated expression of FGF2, which suppressed IFN signaling and facilitated Zika virus infection and spread 42 .…”