6533b861fe1ef96bd12c4c44

RESEARCH PRODUCT

The Sphingosine Kinase-1 Activator, K6PC-5, Attenuates the Ebola Virus Infection and the Virus Induced Cell Death

Fatah KashanchiMadeleine EichlerDagmar Meyer Zu HeringdorfKrishnaraj RajalingamStefan PöhlmannJosef PfeilschifterNerea FerreirósStephan BeckerM. Javad AmanSandra TrautmannGergely ImreVerena Krähling

subject

Programmed cell deathEbola virusSphingosineActivator (genetics)Biologymedicine.disease_causeVirologySphingolipidViruschemistry.chemical_compoundSphingosine kinase 1chemistryViral entrybiology.proteinmedicine

description

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. It has been suggested to play a role in the cytopathic effects induced by the virus. Here we uncover a critical role for sphingolipids in inhibiting viral entry and virus-mediated cytotoxicity. 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 EA.hy926 endothelial-like cells. Furthermore, K6PC-5 inhibited the subsequent necrotic cell death. Finally, K6PC-5 markedly reduced the EBOV titer in infected cells. These data present K6PC‑5 as efficient tool to inhibit EBOV infection in endothelial cells, and suggest further studies to evaluate its systemic effects.

https://doi.org/10.2139/ssrn.3652345