Abstract
ABSTRACTEbolavirus (EBOV) is an RNA virus that is known to cause severe hemorrhagic fever in humans and other primates. EBOV successfully enters and replicates in many cell types. This replication is dependent on the virus successfully coopting a number of cellular factors. Many of these factors are currently unidentified but represent potential targets for antiviral therapeutics. Here we show that cellular polyamines are critical for EBOV replication. We found that small-molecule inhibitors of polyamine synthesis block gene expression driven by the viral RNA-dependent RNA polymerase. Short hairpin RNA (shRNA) knockdown of the polyamine pathway enzyme spermidine synthase also resulted in reduced EBOV replication. These findings led us to further investigate spermidine, a polyamine that is essential for the hypusination of eukaryotic initiation factor 5A (eIF5A). Blocking the hypusination of eIF5A (and thereby inhibiting its function) inhibited both EBOV gene expression and viral replication. The mechanism appears to be due to the importance of hypusinated eIF5A for the accumulation of VP30, an essential component of the viral polymerase. The same reduction in hypusinated eIF5A did not alter the accumulation of other viral polymerase components. This action makes eIF5A function an important gate for proper EBOV polymerase assembly and function through the control of a single virus protein.
Highlights
Ebolavirus (EBOV) and Marburg virus (MARV) are nonsegmented, negative-strand RNA viruses in the Filoviridae family representing two of the most lethal human pathogens known
To identify host factors necessary for EBOV replication, we investigated the effects of small-molecule inhibitors of the polyamine synthesis pathway on EBOV gene expression
Spermine synthase (SMS) converts spermidine to spermine
Summary
Ebolavirus (EBOV) and Marburg virus (MARV) are nonsegmented, negative-strand RNA viruses in the Filoviridae family representing two of the most lethal human pathogens known. The most recent EBOV outbreak that began in 2014 has illustrated our lack of understanding of viral pathogenesis and has highlighted the need for increased study of how the virus replicates. These studies can help us to understand and combat active and dormant filovirus infections. The mammalian polyamine/hypusination pathway has been shown to play a role in the replication of several viruses [8,9,10,11,12,13,14,15,16,17,18]. Several viruses have polyamines present in their capsids to neutralize viral RNA [8], while in other virus infections, intracel-
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