Evolutionary rewiring of host metabolism and interferon signalling by SARS-CoV-2 variants
SARS-CoV-2 variants differ in transmissibility and immune evasion, but their effects on host-cell metabolism and signalling remain less defined.
Using integrated transcriptomic, phosphoproteomic, and amino acid profiling in primary nasal epithelial cells, we compared early and late host responses to pre-Omicron variants (Alpha, Beta), Delta, and Omicron subvariants (BA.1, BA.5). Pre-Omicron strains broadly suppressed antiviral interferon-stimulated gene expression and reprogrammed metabolism by reducing mitochondrial oxidative phosphorylation and β-oxidation.
Delta infection was associated with extensive transcriptional and metabolic remodelling, characterised by activation of stress- and growth-related kinases and selective retention of biosynthetic amino acids, consistent with a host response to stress and viral modulation of interferon-associated signalling.
In contrast, Omicron infection elicited a more restrained response dominated by cytokine and survival pathways, with limited metabolic activation and interferon suppression.
Together, these findings suggest SARS-CoV-2 has progressively evolved toward a strategy that maintains efficient upper-airway replication while minimising epithelial stress and inflammation.
Web | DOI | PDF | Preprint: BioRxiv | Open Access
Efstathios S Giotis; Riaz-Ali Somji; Jonathan C Brown; Shahid Rowles-Khalid; Tukur B Abdullahi; Dongsheng Luo; Natalie Barthel; Michael Mulleder; Markus S Ralser; Wendy S S Barclay; Charalampos Rallis
SARS-CoV-2 variants differ in transmissibility and immune evasion, but their effects on host-cell metabolism and signalling remain less defined.
Using integrated transcriptomic, phosphoproteomic, and amino acid profiling in primary nasal epithelial cells, we compared early and late host responses to pre-Omicron variants (Alpha, Beta), Delta, and Omicron subvariants (BA.1, BA.5). Pre-Omicron strains broadly suppressed antiviral interferon-stimulated gene expression and reprogrammed metabolism by reducing mitochondrial oxidative phosphorylation and β-oxidation.
Delta infection was associated with extensive transcriptional and metabolic remodelling, characterised by activation of stress- and growth-related kinases and selective retention of biosynthetic amino acids, consistent with a host response to stress and viral modulation of interferon-associated signalling.
In contrast, Omicron infection elicited a more restrained response dominated by cytokine and survival pathways, with limited metabolic activation and interferon suppression.
Together, these findings suggest SARS-CoV-2 has progressively evolved toward a strategy that maintains efficient upper-airway replication while minimising epithelial stress and inflammation.
Web | DOI | PDF | Preprint: BioRxiv | Open Access