Analysis of metabolic alterations in carbon utilization pathways during virus infection

Abstract

Viruses are dependent on the metabolic machinery of the host cell to supply the energy and molecular building blocks needed for their replication. Substantial research has focused on understanding how viruses alter host cellular metabolism in the hopes of identifying metabolic pathways that are critical for successful infection. In this thesis, we explore how two viruses important for biodefense, vaccinia virus (VACV) and dengue virus (DENV), manipulate the global cellular metabolome during infection. In Chapter III, we examine the impact VACV has on the host metabolic network and discover that VACV implements a strikingly unique carbon utilization program during infection. Specifically, we define an important role for glutamine during VACV infection and show that glucose is dispensable for replication. We show that the glutaminolytic pathway of glutamine metabolism is markedly altered in VACV-infected cells and is necessary to replenish the TCA cycle during infection. We further demonstrate that glutaminolysis is required for optimal VACV replication by facilitating the robust viral protein synthesis needed for infectious virion production. In Chapter IV, we find that DENV significantly alters glucose metabolism during infection. In particular, we show that DENV infection activates glycolysis via the upregulation of multiple glycolytic mediators. Moreover, we demonstrate that the glycolytic pathway is essential for efficient DENV replication. Therefore, this body of work reveals how viruses dramatically reprogram central carbon metabolism and offers further evidence that metabolic inhibitors may provide promise in the treatment of virus infections in the future.