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. 2023 Jan 27;12:e79946. doi: 10.7554/eLife.79946

Figure 1. Metabolic fingerprint of SARS-CoV-2 infection.

(A) Bubble plot visualization of GO terms enriched by SARS-CoV-2 infection. Epithelial cells were isolated by bronchoalveolar lavage from 6 severe COVID-19 patients compared to 4 healthy patients (lavage). Post-mortem lung biopsies from 2 severe COVID-19 patients compared to surgical biopsies from 2 non-COVID patients (autopsy). Culture sample groups include primary small airway epithelial cells (n=3; alveoli) and primary bronchial epithelial cells (n=3; bronchial) infected with SARS-CoV-2. Enrichment analysis shows immunoinflammatory response, cellular stress (FDR <10–22), and lipid metabolism (FDR <10–5). (B) Venn diagram describing the relationship between differentially expressed genes (DEG), metabolic genes (GO:0008152), and lipid metabolism genes (GO:0006629) in SARS-CoV-2 infection of primary bronchial epithelial cells and COVID-19 patient samples. Across all four sample groups 58 ± 3% of the differentially expressed genes were metabolism-related, with 15 ± 2% of the genes associated with lipid metabolism. (C) Schematic depicting the metabolic landscape of SARS-CoV-2 infection superimposed with a heat map of pathway-associated genes. Red and green boxes indicate gene expression changes following infection in primary bronchial epithelial cells. * marks differentially regulated genes (n=3, FDR <0.05). (D) Schematic of central carbon metabolism and lipid metabolism fluxes superimposed with flux-associated genes. Differentially expressed genes (n=3, FDR <0.01) are marked with *. Genes and associated fluxes are highlighted in red or green for up- or down-regulation, respectively. (E) Microscopic evaluation of primary bronchial epithelial cells infected with SARS-CoV-2 virus or mock control shows an 85% increase in the intracellular accumulation of fluorescent glucose analog (n=3). (F) The ratio of lactate production to glucose uptake (glycolytic index) in SARS-CoV-2 and mock-infected primary cells. Index increases from 1.0 to 1.7 out of 2.0 indicating a transition to glycolysis (i.e. Warburg effect). (G) Microscopic evaluation of primary bronchial epithelial cells infected with SARS-CoV-2 virus or mock control. Neutral lipids (triglycerides) are dyed green while phospholipids are dyed red. Image analysis shows a 23% increase in triglycerides (n=3, p<0.05) and a 41% increase in phospholipids (n=3, p<0.001) following SARS-CoV-2 infection indicating abnormal lipid accumulation in lung epithelium. * p<0.05, ** p<0.01, *** p<0.001.# indicates a small sample size. Bar = 20 µm. Error bars indicate S.E.M.

Figure 1—source data 1. Raw measurements, mean, standard error, and student t-test values were used to create the display items in Figure 1.

Figure 1.

Figure 1—figure supplement 1. Metabolic signature of infection in COVID-19 patients’ samples and SARS-CoV-2 infected primary cells.

Figure 1—figure supplement 1.

(A) Venn diagrams describing the relationship between differentially expressed genes (DEG), metabolic genes (GO:0008152), and lipid metabolism genes (GO:0006629) in COVID-19 patient sample groups including epithelial cells isolated by bronchoalveolar lavage (lavage) and post-mortem lung biopsies (autopsy), as well as primary small airway epithelial cells (alveoli) and primary bronchial epithelial cells (bronchial) infected with SARS-CoV-2. (B) Sunburst graphs showing the coverage of composite metabolic terms (Levy et al., 2016) on general metabolic response induced by SARS-CoV-2 infection. Lipid and mitochondrial metabolism dominate the transcriptional metabolic signature of infection across all four sample groups. (C) Heat map of metabolic genes (Figure 1D) across four sample groups. Red and green boxes are up and downregulated by infection, respectively. # Indicates small sample size. (D) Metabolic analysis of SARS-CoV-2 and mock-infected primary bronchial epithelial cells confirms a 50% increase (n=6, p<0.001) in lactate production 48 hr post-infection. (E) The ratio of lactate production to glucose uptake (glycolytic index) in SARS-CoV-2 and mock-infected primary cells. Index increases from 1.0 to 1.7 out of 2.0 indicating a transition to glycolysis (i.e. Warburg effect: n=6, p<0.01). (F) Schematic depicting ER stress pathways superimposed with pathway-associated genes. Red and green boxes are up and downregulated by infection, respectively. * marks differentially regulated genes (n=3, FDR <0.05). Red and green arrows schematically note interactions based on the transcriptional response. XBP1S is the IRE1 spliced form of XBP1. (G) Heat map of ER stress pathway-associated genes (Figure 1G) across four sample groups. Red and green boxes are up and downregulated by infection, respectively. * p<0.05, ** p<0.01, *** p<0.001 in a two-sided heteroscedastic student’s t-test against control.# indicates a small sample size. Bar = 20 µm. Error bars indicate S.E.M.