Developmental Projects

DP008 Lagunoff

Most antiviral therapy involves targeting specific viral enzymes to halt replication and the drugs are specific to a single virus. However, with less well-characterized viruses or infections during rapid outbreaks, drugs that target multiple viruses would be useful. Host processes that are necessary for viral maintenance or replication of a wide range of viruses could provide novel therapeutic targets. A common host pathway that is necessary for viral spread of many viruses could provide a broad target for general viral infection with one drug. As obligate intracellular parasites viruses rely on host cell metabolism and recent metabolomic studies by our lab and others have identified significant changes in many metabolic pathways induced by different viruses. If multiple virus families required similar metabolic alterations for infection and spread, this would provide a novel therapeutic target for virus outbreaks of unknown origin as might occur in a biodefense setting. In preliminary data we shown that KSHV induces both glycolysis and fatty acid synthesis and both are necessary for the survival of latently infected cells. Interestingly, fatty acid synthesis is also activated by a number of other viruses and is necessary for the replication of other viruses as well, providing proof of concept for targeting pathogenically altered metabolic pathways targeted by multiple viruses. In this proposal we will use metabolomics to identify global changes in host cell metabolic pathways induced by two viruses important for bio-defense, Vaccinia virus, a model for poxvirus infection, and Dengue virus. We will determine which rate-limiting enzymes are altered for the metabolic pathways identified and then inhibit the enzymes to determine which metabolic alterations are necessary for viral spread of these disparate viruses.
Finally, we will use meta analysis of metabolomic data for a number of viruses to determine if there is a common metabolic signature induced by multiple virus families. The ultimate goal is to use systems biology to study metabolic alterations by multiple viruses and determine if viral infections in general can be targeted through the specific inhibition of pathologic host metabolism.