Integrated proteomic and metabolomic profiling characterizes tryptophan metabolic disturbance associated with...

Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus, is associated with high mortality among intensive care unit (ICU) patients; however, the integrated proteomic-metabolomic mechanisms underlying fatal outcomes remain poorly characterized. This prospective cohort study enrolled 68 patients with SFTS, who were admitted to the ICU and classified them as survivors (n = 33) or non-survivors (n = 35) according to their 28-day clinical outcomes. Untargeted metabolomic profiling using ultra-high-performance liquid chromatography-tandem mass spectrometry and quantitative proteomic profiling using data-independent acquisition mass spectrometry were performed on plasma samples collected at ICU admission. Multivariable analysis, pathway enrichment analysis, correlation analysis, and receiver operating characteristic (ROC) curve analysis were used to identify potential prognostic biomarkers and characterize molecular associations. Non-survivors exhibited more severe multi-organ injury and systemic inflammation. Metabolomic profiling revealed marked disruption of tryptophan metabolism: L-tryptophan levels were decreased, whereas kynurenine and its downstream metabolites (kynurenic acid [KA], 3-hydroxyanthranilic acid [3-HAA], xanthurenic acid [XA], and 5-hydroxyindolepyruvate [5-HIP]) were increased, suggesting activation of the kynurenine pathway. The four core tryptophan metabolites yielded a combined area under the curve (AUC) of 0.934 for predicting 28-day mortality and were correlated with indicators of renal function and coagulation. Proteomic profiling identified 200 differentially expressed proteins: proteins upregulated in survivors were enriched in the proteasome pathway, whereas those upregulated in non-survivors were enriched in the IL-17 pathway and other inflammatory and immune pathways. Integrated analysis revealed that the four tryptophan metabolites were associated with 20 differentially expressed proteins, six of which showed robust associations within outcome subgroups. Collectively, tryptophan metabolic disturbances coupled with inflammatory proteomic features may characterize fatal severe SFTS, and the identified metabolite-protein signatures may serve as promising prognostic biomarkers and potential therapeutic targets in critically ill patients.