Enveloped viruses are the causative agent of many persistent and acute infections (e.g. herpes, HIV, hepatitis C, and influenza). They can cause birth defects, encephalitis, cancers, and immunosurppression. Viral infection is the result of multiple complex and intricate interactions between viral factors and host cells, including cellular metabolism. Viruses rely on host cells to provide the building blocks—nucleotides, proteins and lipids—necessary for construction of infectious virus progeny. Even though metabolic processes are critically necessary for virus replications little is known about how most viruses exploit the cellular metabolic and lipid environments. Emphasis in our lab is placed on understanding the cellular metabolic alterations induced by human cytomegalovirus (HCMV) replication. HCMV, a herpesvirus, infects a majority of the world population. It is a significant cause of viral induced birth defects, an opportunistic infection when the immune system is compromised, and a life-threatening complication in transplant patients. HCMV replication requires a global remodeling of cellular metabolism. Research in the lab uses biochemical, molecular, and genetic approaches to analyze the metabolomic and lipidomic dynamics during HCMV replication. It is our goal to use the state of the art “–omics” data generated during our investigations to identify key cellular and viral targets for the development of future antiviral treatments.
HCMV provides a model system for studying how viruses rewire cellular physiology since active replication. It interacts with and modulates various metabolic pathways including lipid synthesis, an important but poorly understood aspect of HCMV biology and, in general, for enveloped viruses. Two guiding questions provide focus for our investigations: (i) How do viruses create a cellular metabolic and lipid environment favorable to infection, and (ii) How may metabolites or lipids contribute to the cellular responses that support or inhibit viral replication?
We discovered that HCMV induces fatty acid elongation. HCMV infection increases the synthesis of very long-chain fatty acids, specifically those with 26 or more carbons. There are seven human fatty acids elongases (ELOVL1-7). They are an important family of enzymes in the fatty acid synthesis pathway; however, their contribution to diseases— especially infectious diseases— have, at best, been understudied. We demonstrated that two, ELOVL5 & 7, are required for efficient viral replication. ELOVL7 produces saturated very long-chain fatty acids that are required for a functional virion envelope. Since our initial observation we have shown that HCMV utilizes multiple mechanisms to increase ELOVL7 activity. Stemming from this previous work our ongoing research investigates the role of ELOVL5 in virus replication, the functions of very long-chain fatty acids and other virally-altered lipids, and the mechanisms that viruses employ to rewire lipid metabolism. We hope to use the resulting information to stop HCMV infections and that the conceptual findings from our investigations will provide understanding into the physiological regulation of lipid metabolism during disease states, include infections with enveloped viruses.
Additionally, a key tool in our studies is mass spectrometry (MS). MS can be employed to answer many questions that are being asked at the interface of basic and clinical sciences. One of the focuses within the lab is to develop protocols and methods to perform MS-based analyses of metabolites and lipids. Our goal is to go beyond cataloguing metabolites and lipids to provide understanding of how disease states, including viral infection, alters cellular metabolic regulation and control.