Human adenovirus serotype 5 infection dysregulates cysteine, purine, and unsaturated fatty acid metabolism in fibroblasts

Viral infections can cause cellular dysregulation of metabolic reactions. Viruses alter host metabolism to meet their replication needs. The impact of viruses on specific metabolic pathways is not well understood, even in well-studied viruses, such as human adenovirus. Adenoviral infection is known to influence cellular glycolysis and respiration; however, global effects on overall cellular metabolism in response to infection are unclear. Furthermore, few studies have employed an untargeted approach, combining emphasis on viral dosage and infection. To address this, we employed untargeted metabolomics to quantify the dynamic metabolic shifts in fibroblasts infected with human adenovirus serotype 5 (HAdV-5) at three dosages (0.5, 1.0, and 2.0 multiplicity of infection [MOI]) and across 4 time points (6-, 12-, 24-, and 36-h post-infection [HPI]). The greatest differences in individual metabolites were observed at 6- and 12-h post-infection, correlating with the early phase of the HAdV-5 infection cycle. In addition to its effects on glycolysis and respiration, adenoviral infection downregulates cysteine and unsaturated fatty acid metabolism while upregulating aspects of purine metabolism. These results reveal specific metabolic pathways dysregulated by adenoviral infection and the associated dynamic shifts in metabolism, suggesting that viral infections alter energetics via profound changes in lipid, nucleic acid, and protein metabolism. The results revealed previously unconsidered metabolic pathways disrupted by HAdV-5 that can alter cellular metabolism, thereby prompting further investigation into HAdV mechanisms and antiviral targeting.