Dynamics of the Cellular Metabolome during Human Cytomegalovirus Infection

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Abstract
Viral replication requires energy and macromolecular precursors derived from the metabolic network of the host cell. Despite this reliance, the effect of viral infection on host cell metabolic composition remains poorly understood. Here we applied liquid chromatography-tandem mass spectrometry to measure the levels of 63 different intracellular metabolites at multiple times after human cytomegalovirus (HCMV) infection of human fibroblasts. Parallel microarray analysis provided complementary data on transcriptional regulation of metabolic pathways. As the infection progressed, the levels of metabolites involved in glycolysis, the citric acid cycle, and pyrimidine nucleotide biosynthesis markedly increased. HCMV-induced transcriptional upregulation of specific glycolytic and citric acid cycle enzymes mirrored the increases in metabolite levels. The peak levels of numerous metabolites during infection far exceeded those observed during normal fibroblast growth or quiescence, demonstrating that HCMV markedly disrupts cellular metabolic homeostasis and institutes its own specific metabolic program. Viruses are parasites. They depend on the biochemical infrastructure of host cells to grow. A key element of the infrastructure provided by the host cell is its metabolic machinery, which viruses rely upon to provide the energy and building blocks necessary for their replication. The way in which viruses interact with host cell metabolism remains, however, poorly understood. The authors have used an advanced measurement technique, liquid chromatography-mass spectrometry, to quantitate directly the levels of a large number of metabolic compounds (energy molecules and biochemical building blocks) during cytomegalovirus infection of cultured human cells. They find that viral infection leads to dramatic increases in the levels of many metabolites and that these increases substantially exceed those associated with normal transitions of cells between resting and growing states. In several cases, enhanced metabolite levels induced by the virus coincide with an apparent increase in host cell production of the machinery (enzymes) involved in making those metabolites. This work represents the first comprehensive characterization of the metabolic environment of virally infected cells and identifies a number of profound metabolic effects of the virus, some of which may eventually prove fruitful targets for antiviral therapy.