Metabolomic atlas of dengue virus infection reveals distinct circulating bioactive lipid signatures

Dengue virus (DENV) appears to manipulate several cellular metabolic pathways to permit its replication and immune evasion in the host. Here, we employed high-resolution mass spectrometry (HR-MS) to investigate the serum metabolomic landscape of clinical DENV infection. Serum specimens from primary dengue (n = 11), secondary dengue (n = 9) samples, and healthy controls (n = 10) were used for untargeted metabolomic quantification on a Waters Xevo G2-XS QTof Mass Spectrometer. The binding potential of selected ligands against DENV NS1, NS3, and NS5 was evaluated. Crystal structures were retrieved from Protein Data Bank and prepared using the Schrodinger's protein preparation wizard. Based on findings from untargeted metabolomics, we validated certain bioactive lipid metabolites using commercial enzyme immunoassays. Serum metabolomic profiling revealed multiple distinct patterns for primary and secondary dengue versus controls. A consistent peak was observed at 2.06 mins across all samples. Certain bioactive lipid metabolites, such as, lysophospholipids, phosphatidylcholines, phosphatidylserines, and phosphatidylinositols, were detected alongside carnitine fragments, ceramides, diacylglycerols (DAGs), and bile acid conjugates in dengue. Molecular docking showed that DAG consistently exhibited strong binding to all the DENV proteins. Notably, lysophosphatidylcholine (LPC) 22:6 showed a selectively strong affinity for NS5. Enzyme validation showed that in the secondary dengue cohort, LPC was significantly elevated than primary and healthy controls (p < 0.05). Our investigations of the metabolomic landscaping, unveiled certain characteristic anabolic shift revealing metabolic vulnerabilities in clinical DENV infection, warranting investigations for use as potential biomarkers of inflammation in disease diagnosis and prognosis.