Metabolomic profiling of dengue infection: unraveling molecular signatures by LC-MS/MS and machine learning models

The progression of dengue fever to severe dengue (SD) is a major public health concern that impairs the capacity of the medical system to predict and treat dengue patients. Hence, the present study used a metabolomic approach integrated with machine models to identify differentially expressed metabolites in patients with SD compared to nonsevere patients and healthy controls.

Comprehensively, the plasma was collected at different clinical phases during dengue without warning signs (DWOW, N = 10), dengue with warning signs (DWW, N = 10), and SD (N = 10) at different stages [i.e., day of admission (DOA), day of defervescence (DOD), and day of convalescent (DOC)] in comparison to healthy control (HC). The samples were subjected to LC‒ESI‒MS/MS to identify metabolites. Statistical and machine learning analyses were performed using R and Python language. Further, biomarker, pathway and correlation analysis was performed to identify potential predictors of dengue.

A total of 423 metabolites were identified in all the study groups. Paired and unpaired t-tests revealed 14 highly differentially expressed metabolites between and across the dengue groups, with four metabolites (shikimic acid, ureidosuccinic acid, propionyl carnitine, and alpha-tocopherol) showing significant differences compared to HC. Furthermore, biomarker (ROC) analysis revealed 11 potential molecules with a significant AUC value of 1 that could serve as potential biomarkers for identifying different dengue clinical stages that are beneficial for predicting dengue disease outcomes. The logistic regression model revealed that S-adenosylhomocysteine, hypotaurine, and shikimic acid metabolites could be beneficial indicators for predicting severe dengue, with an accuracy and AUC of 0.75. The data showed that dengue infection is related to lipid metabolism, oxidative stress, inflammation, metabolomic adaptation, and virus manipulation. Moreover, the biomarkers had a significant correlation with biochemical parameters like platelet count, and hematocrit. These results shed some light on host-derived small-molecule biomarkers that are associated with dengue severity and novel insights into metabolomics mechanisms interlinked with disease severity.