Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy.
Viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks for viral replication. We developed a flux measurement approach based on liquid chromatography-tandem mass spectrometry to quantify changes in metabolic activity induced by human cytomegalovirus (HCMV). This approach reliably elucidated fluxes in cultured mammalian cells by monitoring metabolome labeling kinetics after feeding cells (13)C-labeled forms of glucose and glutamine. Infection with HCMV markedly upregulated flux through much of the central carbon metabolism, including glycolysis. Particularly notable increases occurred in flux through the tricarboxylic acid cycle and its efflux to the fatty acid biosynthesis pathway. Pharmacological inhibition of fatty acid biosynthesis suppressed the replication of both HCMV and influenza A, another enveloped virus. These results show that fatty acid synthesis is essential for the replication of two divergent enveloped viruses and that systems-level metabolic flux profiling can identify metabolic targets for antiviral therapy.
Munger
Joshua
J
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
Bennett
Bryson D
BD
Parikh
Anuraag
A
Feng
Xiao-Jiang
XJ
McArdle
Jessica
J
Rabitz
Herschel A
HA
Shenk
Thomas
T
Rabinowitz
Joshua D
JD
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000378:metabolism; D003198:Computer Simulation; D003587:Cytomegalovirus / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018511:Systems Integration
D000998:Antiviral Agents; D015415:Biomarkers; D005227:Fatty Acids