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Influenza virus entry via the GM3 ganglioside-mediated platelet-derived growth factor receptor β signalling pathway

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  • Influenza virus entry via the GM3 ganglioside-mediated platelet-derived growth factor receptor β signalling pathway

    J Gen Virol. 2019 Feb 14. doi: 10.1099/jgv.0.001235. [Epub ahead of print]
    Influenza virus entry via the GM3 ganglioside-mediated platelet-derived growth factor receptor β signalling pathway.

    Vrijens P1, Noppen S1, Boogaerts T1, Vanstreels E1, Ronca R2, Chiodelli P2, Laporte M1, Vanderlinden E1, Liekens S1, Stevaert A1, Naesens L1.
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    Abstract

    The possible resistance of influenza virus against existing antiviral drugs calls for new therapeutic concepts. One appealing strategy is to inhibit virus entry, in particular at the stage of internalization. This requires a better understanding of virus-host interactions during the entry process, including the role of receptor tyrosine kinases (RTKs). To search for cellular targets, we evaluated a panel of 276 protein kinase inhibitors in a multicycle antiviral assay in Madin-Darby canine kidney cells. The RTK inhibitor Ki8751 displayed robust anti-influenza A and B virus activity and was selected for mechanistic investigations. Ki8751 efficiently disrupted the endocytic process of influenza virus in different cell lines carrying platelet-derived growth factor receptor β (PDGFRβ), an RTK that is known to act at GM3 ganglioside-positive lipid rafts. The more efficient virus entry in CHO-K1 cells compared to the wild-type ancestor (CHO-wt) cells indicated a positive effect of GM3, which is abundant in CHO-K1 but not in CHO-wt cells. Entering virus localized to GM3-positive lipid rafts and the PDGFRβ-containing endosomal compartment. PDGFRβ/GM3-dependent virus internalization involved PDGFRβ phosphorylation, which was potently inhibited by Ki8751, and desialylation of activated PDGFRβ by the viral neuraminidase. Virus uptake coincided with strong activation of the Raf/MEK/Erk cascade, but not of PI3K/Akt or phospholipase C-γ. We conclude that influenza virus efficiently hijacks the GM3-enhanced PDGFRβ signalling pathway for cell penetration, providing an opportunity for host cell-targeting antiviral intervention.


    PMID: 30762518 DOI: 10.1099/jgv.0.001235
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