The Filoviridae are a small family of viruses that include the highly pathogenic Ebola and Marburg viruses. These viruses are associated with fatality rates of up to 90%. As has been highlighted during the recent outbreaks of Ebola in Western Africa, filoviruses have tremendous potential for adverse health effects both directly (through direct pathogenesis) and indirectly (forcing the shutdown of existing clinics and treatment programs, sparking panic). Though a variety of potential therapies for the disease have been developed and deployed, it is currently unclear which if any have helped. A clear lesson from the outbreak is that the lack of basic information about viruses like Ebola have hampered effective control and therapy. In this vein, it is clear that basic aspects of how Ebola and its relatives utilize components of infected cells to their advantage are still unknown. A detailed understanding of how Ebola steals from its host or identification of cellular processes that the virus requires can offer important insight into both the general biology of the virus and can lead to the identification of host processes that can be effectively targeted to block viral replication. This proposal will test the hypothesis that polyamines and products of polyamines such as the non-canonical amino acid hypusine are essential for Ebola virus replication. To test this hypothesis we will use existing small- molecules that target the polyamine synthesis pathway and we will use gene-targeting knockdown technology to assess the importance of polyamine synthesis enzymes, hypusination enzymes and the hypusinated protein eIF5A on Ebola virus gene expression. Through these studies we hope to determine the importance of this pathway for viral gene expression and understand the mechanism by which the polyamine pathway controls viral gene expression. Identification of this pathway as important for Ebola virus replication has significant translational implications, as there are many compounds that are known to target the polyamine and hypusine synthesis pathways. Some of these are FDA-approved, some are in advanced development. Data supporting our hypothesis that this pathway is important can lead to the testing of these compounds in animal models of disease.
This proposal will investigate how cellular polyamines are used by Ebola virus. Polyamines are small basic molecules inside the cell that our data suggests are important for the Ebola virus to make copies of itself. We will investigate how the virus uses these cellular pieces to its own advantage and determine whether small molecules that decreases cellular polyamines will block Ebola virus replication.
