The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection
Gergely Imre,
Verena Krähling,
Madeleine Eichler,
Sandra Trautmann,
Nerea Ferreirós,
M. Javad Aman,
Fatah Kashanchi,
Krishnaraj Rajalingam,
Stefan Pöhlmann,
Stephan Becker,
Dagmar Meyer zu Heringdorf,
Josef Pfeilschifter
Affiliations
Gergely Imre
Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany; Corresponding author
Verena Krähling
Institute of Virology, Philipps University Marburg, Marburg, Germany; German Center for Infection Research (DZIF), partner site Gießen–Marburg–Langen, Marburg, Germany
Madeleine Eichler
Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
Sandra Trautmann
Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
Nerea Ferreirós
Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
M. Javad Aman
Integrated BioTherapeutics, Inc., Gaithersburg, MD 20850, USA
Fatah Kashanchi
Laboratory of Molecular Virology, George Mason University Manassas, VA 20110, USA
Krishnaraj Rajalingam
Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Stefan Pöhlmann
Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany
Stephan Becker
Institute of Virology, Philipps University Marburg, Marburg, Germany; German Center for Infection Research (DZIF), partner site Gießen–Marburg–Langen, Marburg, Germany
Dagmar Meyer zu Heringdorf
Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
Josef Pfeilschifter
Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
Summary: 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.
