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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
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Varicella-zoster virus requires a functional PI3K/Akt/GSK-3alpha/beta signaling cascade for efficient replication

Markus Rahaus1, Nathalie Desloges, Manfred H Wolff

  • 1Institute of Microbiology and Virology, Private University of Witten/Herdecke gGmbH, Stockumer Strasse 10, D-58448 Witten, Germany. rahaus@uni-wh.de

Cellular Signalling
|August 29, 2006
PubMed

Insights

Varicella-zoster virus (VZV) replication depends on host cell survival pathways. VZV infection activates the Akt signaling cascade, crucial for viral replication, and VZV kinases promote this activation.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Varicella-zoster virus (VZV) replication requires overcoming host defenses.
  • Host cell signaling pathways, particularly the Akt cascade, regulate apoptosis and cell survival, impacting viral replication.
  • The Akt pathway influences key factors like Bad, FOXO1, mTor, and GSK-3alpha/beta, controlling cell death, cell cycle, and translation.

Purpose of the Study:

  • To investigate the role of the PI3K/Akt/GSK-3alpha/beta signaling pathway in VZV replication.
  • To determine the impact of VZV infection and VZV kinases (pORFs 47 and 66) on Akt pathway activation.
  • To assess the effect of inhibiting key signaling molecules on VZV replication and apoptosis.

Main Methods:

  • VZV infection of MeWo cells and analysis of Akt and related protein phosphorylation levels.
  • Pharmacological inhibition of PI3K, Akt, and GSK-3alpha/beta pathways before VZV infection.
  • Transfection studies using VZV kinases (pORFs 47 and 66) and infection with VZV deletion mutants (VZVDelta47, VZVDelta66).

Main Results:

  • VZV infection significantly increased Akt phosphorylation (9-18 fold) independently of PI3K phosphorylation patterns.
  • Phosphorylation of Bad decreased, while mTor and FOXO1 phosphorylation increased during VZV infection; GSK-3alpha/beta phosphorylation remained stable.
  • Inhibition of PI3K, Akt, or GSK-3alpha/beta severely reduced viral replication, and Akt inhibition increased apoptosis.
  • VZV kinases pORFs 47 and 66 enhanced Akt phosphorylation, and their absence (VZVDelta47, VZVDelta66) reduced Akt and GSK-3alpha/beta phosphorylation.

Conclusions:

  • The PI3K/Akt/GSK-3alpha/beta signaling pathway is essential for successful VZV replication.
  • VZV kinases pORFs 47 and 66 play a key role in activating this crucial host signaling pathway for viral propagation.

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