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.

The spike of SARS-CoV-2 promotes metabolic rewiring in hepatocytes

“…Experiments performed in human primary hepatocytes further evidenced a modulation of intracellular glucose and extracellular lactate upon infection. These data are consistent with previous work showing that viral infection promotes glycolysis 62 . Remarkably, in our fluxomics results performed with the primary hepatocytes, infection resulted in an increase of fumarate and malate.…”

Integration of omics data to generate and analyse COVID-19 specific genome-scale metabolic models

“…However, because this model only incorporated a SARS-CoV-2 virus biomass target function (VBOF) into a GEM of human alveolar macrophages, its predictive power could be further improved by fitting metabolic constraints to the diseased state of a metabolic network. A similar approach of modelling the infection in the hepatocyte-derived cellular carcinoma cell line Huh7 using the manual extension of the Recon 2.2 model was reported by Yaneske et al [ 8 ].…”

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity

“…Application of GSMM by integrating the host transcriptomics and metabolomics and the virus biomass function can provide information about the altered metabolic reactions. Earlier seminal studies in the context of SARS-CoV-2, based on host-virus GSMM of human alveolar macrophages (Renz et al, 2020), human airway epithelial cells (Bannerman et al, 2021), and liver cancer cells (Huh7) (Yaneske et al, 2021), reported that the role of biosynthesis and degradation of amino acids, glycolytic shift, and energy metabolism are essential for progressive viral replication. As the SARS-CoV-2 was not detected in the blood cell populations in our cohort, we therefore hypothesized that the systemic metabolic alterations are most likely because of the bystander effect of the infection due to the inflammatory conditions.…”