Secretome Screening Reveals Fibroblast Growth Factors as Novel Inhibitors of Viral Replication

Abstract

Cellular antiviral programs can efficiently inhibit viral infection. These programs are often initiated through signaling cascades induced by secreted proteins such as type I interferons, IL-6 or TNF-α. Here, we generated an arrayed library of 756 human secreted proteins to perform a secretome screen focused on the discovery of novel modulators of viral entry and/or replication. The individual secreted proteins were tested for their capacity to inhibit infection by two replication-competent recombinant vesicular stomatitis viruses (VSV) with distinct glycoproteins utilizing different entry pathways. Fibroblast growth factor 16 (FGF16) was identified and confirmed as the most prominent novel inhibitor of both VSVs and therefore of viral replication and not entry. Importantly, an antiviral interferon signature was completely absent in FGF16 treated cells. Nevertheless, the antiviral effect of FGF16 is broad as it was evident on multiple cell types and also on infection of Coxsackievirus. In addition, other members of the FGF family also inhibited viral infection. Thus, our unbiased secretome screen revealed a novel protein family capable of inducing a cellular antiviral state. This previously unappreciated role of the FGF family may have implications for the development of new antivirals and the efficacy of oncolytic virus therapy.Viruses infect human cells in order to replicate, while human cells aim to resist infection. Several cellular antiviral programs have therefore evolved to resist infection. Knowledge of these programs is essential for the design of antiviral therapeutics in the future. The induction of antiviral programs is often initiated by secreted proteins such as interferons. We hypothesized that other secreted proteins may also promote resistance to viral infection. Thus we tested 756 human secreted proteins for their capacity to inhibit two pseudotypes of vesicular stomatitis virus (VSV). In this first secretome screen on viral infection we identified fibroblast growth factor 16 (FGF16) as a novel antiviral against multiple VSV pseudotypes as well as Coxsackievirus. Subsequent testing of other FGF family members revealed that FGF signaling generally inhibits viral infection. This finding may lead to the development of new antivirals and may also be applicable to enhance oncolytic virus therapy.

Reciprocal Effects of Fibroblast Growth Factor Receptor Signaling on Dengue Virus Replication and Virion Production

“…For instance, knockdown of FGFR4 was reported to limit influenza virus entry and replication, while knockdown of FGFR1 promoted its replication (Kö nig et al, 2010;Liu et al, 2015). Moreover, ligand-induced stimulation of the FGFR pathway inhibited replication of Coxsackievirus and vesicular stomatitis virus (van Asten et al, 2018). Here we show that several flaviviruses (all four DENV serotypes and two ZIKV lineages) are influenced by FGFR signaling.…”

Epigenetic Regulator miRNA Pattern Differences Among SARS-CoV, SARS-CoV-2, and SARS-CoV-2 World-Wide Isolates Delineated the Mystery Behind the Epic Pathogenicity and Distinct Clinical Characteristics of Pandemic COVID-19

“…To identify which pathways are associated with SARS-CoV and SARS-CoV infection, we have performed the gene ontology (GO) and pathway functional enrichment of the targeted genes using different tools. This revealed a myriad of significant functions and pathways involved in host immune responses, such as Wnt signaling (Ljungberg et al, 2019 ), MAPK signaling (Kimura et al, 2013 ), T-cell-mediated immunity (Channappanavar et al, 2014 ), autophagy (Yordy and Iwasaki, 2011 ), FGF receptor binding (van Asten et al, 2018 ), TGF-beta signaling (Denney et al, 2018 ), VEGF signaling (Alkharsah, 2018 ), ErbB signaling (Zheng et al, 2014 ), mTOR signaling (Le Sage et al, 2016 ), and TNF-alpha signaling (Kimura et al, 2013 ) are particularly targeted by SARS-CoV-2 ( Figures 7A–E ).…”

Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19

“…To identify which pathways are associated with SARS-CoV and SARS-CoV infection, we have performed the gene ontology (GO) and pathway functional enrichment of the targeted genes using different tools. This reveals a myriad of significant functions and pathways involved in host immune responses, like-Wnt signaling (Ljungberg et al, 2019), MAPK signaling (Kimura et al, 2013), T cell-mediated immunity (Channappanavar et al, 2014), autophagy (Yordy and Iwasaki, 2011), FGF receptor binding (van Asten et al, 2018), TGF-beta signaling (Denney et al, 2018), VEGF signaling (Alkharsah, 2018), ErbB signaling (Zheng et al, 2014), mTOR signaling (Le Sage et al, 2016), TNF-alpha signaling (Kimura et al, 2013), etc are particularly targeted by SARS-CoV-2 (Figure 7A-7E).…”