Metabolic Alterations in COVID-19 Pathophysiology

Infection with SARS-CoV-2 precipitates profound shifts in host metabolism, reflecting both viral demand for biosynthetic substrates and the host’s immune and inflammatory responses. Central carbon metabolism is reprogrammed towards glycolysis and the pentose phosphate pathway, supporting rapid production of nucleotides and reducing equivalents. Amino acid catabolism, notably of arginine and tryptophan, is altered, driving immunomodulatory effects through metabolites such as nitric oxide and kynurenine. Lipid remodelling becomes apparent in circulating lipoproteins and free fatty acids, contributing to membrane synthesis for virion assembly and influencing inflammatory signalling. Dysregulated redox balance, as evidenced by elevated markers of oxidative stress, underpins tissue injury and endothelial dysfunction. In severe disease, these metabolic derangements accompany exaggerated cytokine release, aberrant neutrophil activity and coagulopathy. Together, these pathways offer mechanistic insight into organ injury, long-term sequelae and potential metabolic targets for therapeutic intervention.

Research from Nature Portfolio

Recent studies have detailed immune-cell intrinsic metabolic derangements in severe COVID-19. Analysis of neutrophil metabolomes revealed suppression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, redirecting flux into the pentose phosphate pathway and driving neutrophil extracellular trap (NET) formation under oxidative stress. This work highlights a cell-intrinsic metabolic checkpoint that controls NET-mediated tissue injury. Complementary multi-omic profiling of serum from mild and severe patients has uncovered tight correlations between metabolites and proinflammatory cytokines. Arginine, tryptophan and purine pathways emerged as central nodes in cytokine release syndrome, and experimental modulation of these pathways in ex vivo immune cells attenuated hyperinflammation, suggesting that metabolic interventions can recalibrate pathological immune responses.

Metabolic Alterations in COVID-19 Pathophysiology publication trend

The graph below shows the total number of articles in metabolic alterations in covid-19 pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Metabolome: The complete set of small-molecule metabolites present in a biological sample.

Pentose phosphate pathway: A metabolic route parallel to glycolysis that generates NADPH and five-carbon sugars for biosynthesis and redox homeostasis.

Neutrophil extracellular traps (NETs): Web-like structures of DNA and proteins released by neutrophils to trap pathogens, which can also contribute to tissue damage.

Cytokine release syndrome (CRS): A hyperinflammatory state characterised by elevated levels of circulating cytokines leading to multi-organ dysfunction.

Multi-omics: Integrated analysis of diverse molecular datasets, such as genomics, proteomics and metabolomics, to gain comprehensive insight into biological systems.

References

1. Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation. Nature Communications (2023).
2. Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications. Nature Communications (2021).
3. The landscape of abnormal pathway activation confers COVID-19 patients' molecular sequelae earlier than clinical phenotype. Theranostics (2023).
4. Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial. Pharmacological Research (2023).
5. Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia. Critical Care (2024).