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

J Gen Virol. 2019 Apr;100(4):583-601. doi: 10.1099/jgv.0.001235. Epub 2019 Feb 14.


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.

Keywords: antiviral; ganglioside; influenza virus; platelet-derived growth factor receptor; receptor tyrosine kinase; virus entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Dogs
  • G(M3) Ganglioside / metabolism*
  • HEK293 Cells
  • Humans
  • Influenza, Human / drug therapy
  • Influenza, Human / metabolism*
  • Influenza, Human / virology*
  • Madin Darby Canine Kidney Cells
  • Orthomyxoviridae / drug effects
  • Orthomyxoviridae / pathogenicity*
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / metabolism*
  • Phenylurea Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / physiology
  • Protein Kinase Inhibitors / pharmacology
  • Quinolines / pharmacology
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Virus Internalization / drug effects


  • G(M3) Ganglioside
  • N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor beta