Genome‐scale metabolic modelling of SARS‐CoV‐2 in cancer cells reveals an increased shift to glycolytic energy production

Abstract

Cancer is considered a high‐risk condition for severe illness resulting from COVID‐19. The interaction between severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) and human metabolism is key to elucidating the risk posed by COVID‐19 for cancer patients and identifying effective treatments, yet it is largely uncharacterised on a mechanistic level. We present a genome‐scale map of short‐term metabolic alterations triggered by SARS‐CoV‐2 infection of cancer cells. Through transcriptomic‐ and proteomic‐informed genome‐scale metabolic modelling, we characterise the role of RNA and fatty acid biosynthesis in conjunction with a rewiring in energy production pathways and enhanced cytokine secretion. These findings link together complementary aspects of viral invasion of cancer cells, while providing mechanistic insights that can inform the development of treatment strategies.

Abstract

Summary of main metabolic changes in SARS‐CoV‐2‐infected Huh7 cells at 72 hpi. The mitochondrial ETC and oxidative phosphorylation are downregulated, reducing ATP production from the TCA cycle but potentially providing protection from apoptosis. The components of the TCA producing intermediates for viral amino acid synthesis are upregulated. While the production of ATP is reduced in the TCA, the energy‐producing reactions of glycolysis are upregulated, producing ATP for the viral production of amino acids and RNA. Fatty acid synthesis is also upregulated, producing fatty acids for the synthesis of the viral envelope. The production of anti‐inflammatory polyunsaturated fatty acids and the electron transport chain are both downregulated. Upregulation of inflammatory proteins IP10, eotaxin, MIP‐1β and IL‐6 has been linked with the cytokine storm. AGP is an acute‐phase protein involved in the inflammatory response. Green upward arrows represent upregulation. Red downward arrows represent downregulation. (A) Upregulated transcriptomic‐informed flux reactions involved in RNA production. (B) Dysregulated transcriptomic‐informed flux reactions involved in oxidative phosphorylation and glycolysis. (C) Visual overview of main metabolic changes. (D) Dysregulated transcriptomic‐informed flux reactions involved in fatty acid metabolism; RE3243R, production of polyunsaturated fatty acids, for example oleic acid; C183806m, final step of β‐oxidation producing octanyl‐CoA; C163C143m, first step of β‐oxidation; ETF/QO, electron transfer from octanoyl‐CoA to ubiquinone. (E) Upregulated transcriptomic‐informed secretory pathways involved in the immune response. PPP, pentose phosphate pathway; FAS, fatty acid synthesis; FA, fatty acid, TCA, citric acid cycle; AA, amino acid; FA‐β‐oxidation, fatty acid‐β‐oxidation; ETC, electron transport chain; PUFA, polyunsaturated fatty acid; IP10, interferon γ‐induced protein‐10; AGP, alpha‐1 acid glycoprotein; IL‐6, interleukin 6; MIP‐1β, macrophage inflammatory protein‐1β; TDK, deoxyuridine kinase; TK, thymidine kinase; NDPK, NDP kinase; C183806m, FAOXC183806m; C163C143m, FAOXC163C143m; ETF/QO, electron transfer flavoprotein/electron transfer flavoprotein–ubiquinone oxidoreductase, CI, NADH: ubiquinone oxidoreductase; CII, succinate dehydrogenase; CIII, cytochrome reductase; CIV, cytochrome c oxidase; CV, ATP synthase; PFK, phosphofructokinase; ALDD2, aldehyde dehydrogenase.