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

doi:10.1016/j.isci.2021.102266

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. eCollection 2021 Apr 23.

Authors

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.

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.