An essential role of PI3K in the control of West Nile virus infection

Sci Rep. 2017 Jun 16;7(1):3724. doi: 10.1038/s41598-017-03912-5.

Abstract

The phosphatidyl-inositol-3 kinases (PI3K) pathway regulates a variety of cellular processes, including cell proliferation, RNA processing, protein translation, autophagy, apoptosis and antiviral immunity. Many viruses depend on PI3K signaling for replication. However, its role in flaviviral infection has not been clearly defined. Here we report that PI3K signaling is critical for the control of West Nile virus (WNV) infection by regulating type I IFN (IFN-I) response. Inhibition of PI3K activity by 3-methyl adenine (3-MA), Wortmannin (WM) and LY294002 (LY) increased viral titers by 3-16 folds in primary mouse macrophages, embryonic fibroblasts and human cell lines. Both 3-MA and LY repressed IFN-I mRNA and protein expression significantly. Surprisingly, WM enhanced the mRNA expression of IFN-I and TNF-α, and TNF-α protein production modestly, while dramatically decreased the secreted IFN-I. Further studies showed that the catalytic subunit p110δ of class I PI3K played a role in induction of antiviral immune responses. Lastly translocation of interferon regulatory factor 7(IRF7) from the cytosol to the nuclei was effectively blocked in the presence of PI3K inhibitors. Our results clearly define an antiviral role of PI3K by modulating immune responses and demonstrate differential mode of action of three PI3K inhibitors on IFN-I.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Humans
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Binding
  • Signal Transduction
  • West Nile Fever / metabolism*
  • West Nile Fever / virology*
  • West Nile virus / physiology*

Substances

  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Phosphatidylinositol 3-Kinases