The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection

  • iScience. 2021 Mar 5;24(4):102266. doi: 10.1016/j.isci.2021.102266.
Gergely Imre  1 ,  Verena Krähling  2  3 ,  Madeleine Eichler  1 ,  Sandra Trautmann  4 ,  Nerea Ferreirós  4 ,  M Javad Aman  5 ,  Fatah Kashanchi  6 ,  Krishnaraj Rajalingam  7 ,  Stefan Pöhlmann  8  9 ,  Stephan Becker  2  3 ,  Dagmar Meyer Zu Heringdorf  1 ,  Josef Pfeilschifter  1
Affiliations
  • 1. Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany.
  • 2. Institute of Virology, Philipps University Marburg, Marburg, Germany.
  • 3. German Center for Infection Research (DZIF), partner site Gießen-Marburg-Langen, Marburg, Germany.
  • 4. Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany.
  • 5. Integrated BioTherapeutics, Inc., Gaithersburg, MD 20850, USA.
  • 6. Laboratory of Molecular Virology, George Mason University Manassas, VA 20110, USA.
  • 7. Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • 8. Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.
  • 9. Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany.
PMID: 33817572 DOI: 10.1016/j.isci.2021.102266
Abstract

Ebola virus (EBOV) is responsible for outbreaks with case fatality rates of up to 90% and for an epidemic in West Africa with more than ten thousand deaths. EBOV glycoprotein (EBOV-GP) is the only viral surface protein and is responsible for viral entry into cells. Here, by employing pseudotyped EBOV-GP viral particles, we uncover a critical role for sphingolipids in inhibiting viral entry. Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). The administration of the SphK1 Activator, K6PC-5, or S1P, or the overexpression of SphK1 consistently exhibited striking inhibitory effects in EBOV-GP-driven entry in diverse cell lines. Finally, K6PC-5 markedly reduced the EBOV titer in infected cells and the de novo production of Viral Proteins. These data present K6PC-5 as an efficient tool to inhibit EBOV Infection in endothelial cells and suggest further studies to evaluate its systemic effects.

Keywords
Cell Biology; Molecular Microbiology; Virology.
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