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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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Influence of sphingosine-1-phosphate signaling on HCMV replication in human embryonal lung fibroblasts

Anika Zilch1, Christian Rien1, Cynthia Weigel2,3

  • 1Section Experimental Virology, Institute of Medical Microbiology, University Hospital Jena, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745, Jena, Germany.

Medical Microbiology and Immunology
|April 28, 2018
PubMed

Insights

Human cytomegalovirus (HCMV) replication relies on sphingosine-1-phosphate (S1P) signaling pathways. Targeting these host cell pathways, particularly S1PR2, offers a promising strategy for novel antiviral drug development against HCMV.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Human cytomegalovirus (HCMV) causes severe disease in immunocompromised individuals and congenital infections.
  • Current antiviral drugs targeting viral proteins have limitations including toxicity and resistance.
  • Host cell molecules, particularly bioactive sphingolipids, are crucial for HCMV replication.

Purpose of the Study:

  • To investigate the role of sphingosine-1-phosphate (S1P) signaling in HCMV replication within human embryonal lung fibroblasts (HELF).
  • To identify specific sphingolipid pathways and receptors involved in supporting viral replication.
  • To explore the potential of targeting S1P signaling as a novel antiviral strategy.

Main Methods:

  • Analysis of HCMV replication in HELF cells under conditions of sphingosine kinase (SK) inhibition and S1P modulation.
  • Application of extracellular S1P, anti-S1P antibodies, and specific sphingosine-1-phosphate receptor (S1PR) antagonists (FTY720, JTE-013).
  • Investigation of the role of Rac-1 signaling pathway components (Rac-1, PAK1) in HCMV replication.

Main Results:

  • HCMV replication was dependent on the functional activity of sphingosine kinases (SK).
  • Restoration of viral replication was observed upon addition of extracellular S1P during SK inhibition.
  • Neutralization of extracellular S1P and inhibition of S1PR2 significantly decreased HCMV replication.
  • Inhibition of Rac-1 activity reduced viral replication, while PAK1 inhibition had no effect.

Conclusions:

  • Sphingosine-1-phosphate (S1P) signaling is essential for efficient human cytomegalovirus (HCMV) replication.
  • S1PR2 and Rac-1 pathways are critical host factors supporting HCMV infection.
  • Targeting S1P-induced pathways presents a viable strategy for developing new antiviral therapies against HCMV.
Keywords:
Antiviral therapyHCMVRac-1Sphingosine kinaseSphingosine phosphateSphingosine phosphate receptor

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