{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:52:13Z","timestamp":1791525133226,"version":"4.3.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2013metabolomic 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\u2013tandem 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\u2013protein signatures may serve as promising prognostic biomarkers and potential therapeutic targets in critically ill patients.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1898053","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:35:21Z","timestamp":1791524121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated proteomic and metabolomic profiling characterizes tryptophan metabolic disturbance associated with mortality in ICU-admitted SFTS patients"],"prefix":"10.3389","volume":"17","author":[{"given":"Li","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puhui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Yantai Qishan Hospital","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanzhen","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Yantai Qishan Hospital","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxiao","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxue","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1010095","article-title":"Fever with thrombocytopenia associated with a novel Bunyavirus in China","volume":"364","author":"Yu","year":"2011","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.3892\/ijmm.2025.5610","article-title":"Current status of severe fever with thrombocytopenia syndrome in China (Review)","volume":"56","author":"Sun","year":"2025","journal-title":"Int J Mol Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e33611","article-title":"Viral shedding pattern of severe fever with thrombocytopenia syndrome virus in severely ill patients: A prospective, multicenter cohort study","volume":"10","author":"Hu","year":"2024","journal-title":"Heliyon"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0013249","article-title":"Precise staging of severe fever with thrombocytopenia syndrome: Integrating the extent of organ damage for prognostic and therapeutic applications","volume":"19","author":"Hao","year":"2025","journal-title":"PloS NeglTrop Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1693946","article-title":"Serum proteomics and machine learning identify PSMD11 as a prognostic biomarker in severe fever with thrombocytopenia syndrome","volume":"16","author":"Zhao","year":"2025","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02583-20","article-title":"Molecular signatures of inflammatory profile and B-cell function in patients with severe fever with thrombocytopenia syndrome","volume":"12","author":"Park","year":"2021","journal-title":"mBio"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/metabo15040228","article-title":"Metabolic profiling reveals potential prognostic biomarkers for SFTS: Insights into disease severity and clinical outcomes","volume":"15","author":"Zhu","year":"2025","journal-title":"Metabolites"},{"key":"B8","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.cell.2021.12.040","article-title":"Complement activation induces excessive T cell cytotoxicity in severe COVID-19","volume":"185","author":"Georg","year":"2022","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"6778","DOI":"10.1038\/s41467-024-51074-6","article-title":"Multi-omics characterization of the monkeypox virus infection","volume":"15","author":"Huang","year":"2024","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4732","DOI":"10.1038\/s41467-025-59565-w","article-title":"Multi-omics analysis of SFTS virus infection in Rhipicephalus microplus cells reveals antiviral tick factors","volume":"16","author":"Petit","year":"2025","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70718-2","article-title":"Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis","volume":"14","author":"Liu","year":"2014","journal-title":"Lancet Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-024-02285-2","article-title":"Metabolic alterations in urine among the patients with severe fever with thrombocytopenia syndrome","volume":"21","author":"Zhang","year":"2024","journal-title":"Virol J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.06.004","article-title":"Tryptophan metabolism in health and disease","volume":"35","author":"Xue","year":"2023","journal-title":"Cell Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf9794","article-title":"Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health","volume":"357","author":"Cervenka","year":"2017","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41573-019-0016-5","article-title":"Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond","volume":"18","author":"Platten","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"B16","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1186\/s12879-022-07582-1","article-title":"The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis","volume":"22","author":"Almulla","year":"2022","journal-title":"BMC Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140327","article-title":"COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status","volume":"5","author":"Thomas","year":"2020","journal-title":"JCI Insight"},{"key":"B18","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1097\/SHK.0b013e31819714fa","article-title":"Increased plasma kynurenine values and kynurenine-tryptophan ratios after major trauma are early indicators for the development of sepsis","volume":"32","author":"L\u00f6gters","year":"2009","journal-title":"Shock"},{"key":"B19","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"32ra36","DOI":"10.1126\/scitranslmed.3000632","article-title":"Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease","volume":"2","author":"Favre","year":"2010","journal-title":"Sci Transl Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2012.09.006","article-title":"An expanding range of targets for kynurenine metabolites of tryptophan","volume":"34","author":"Stone","year":"2013","journal-title":"Trends Pharmacol Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abf8483","article-title":"Kynurenic acid may underlie sex-specific immune responses to COVID-19","volume":"14","author":"Cai","year":"2021","journal-title":"Sci Signal"},{"key":"B23","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1113\/jphysiol.2003.055913","article-title":"Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications","volume":"555","author":"Berry","year":"2004","journal-title":"J Physiol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40124","article-title":"Uric acid promotes an acute inflammatory response to sterile cell death in mice","volume":"120","author":"Kono","year":"2010","journal-title":"J Clin Invest"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1128(200103)21:2<105::AID-MED1002>3.0.CO;2-U","article-title":"Adenosine deaminase: functional implications and different classes of inhibitors","volume":"21","author":"Cristalli","year":"2001","journal-title":"Med Res Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.4c00281","article-title":"Adenosine deaminase as a potential diagnostic and prognostic biomarker for severe fever with thrombocytopenia syndrome","volume":"9","author":"Ye","year":"2024","journal-title":"ACS Omega"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/metabo15090608","article-title":"Metabolomics and cytokine signatures in COVID-19: uncovering immunometabolism in pathogenesis","volume":"15","author":"Banoei","year":"2025","journal-title":"Metabolites"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015060621","article-title":"Developmental origins for kidney disease due to shroom3 deficiency","volume":"27","author":"Khalili","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.pediatrneurol.2025.03.012","article-title":"Glycosylphosphatidylinositol biosynthesis defect due to novel biallelic pathogenic variants in PIGW","volume":"167","author":"Rabouhi","year":"2025","journal-title":"Pediatr Neurol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2125","article-title":"Matrix metalloproteinases and the regulation of tissue remodelling","volume":"8","author":"Page-McCaw","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071362","article-title":"Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle","volume":"297","author":"Lee","year":"2002","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ydbio.2015.06.005","article-title":"A thioredoxin fold protein Sh3bgr regulates Enah and is necessary for proper sarcomere formation","volume":"405","author":"Jang","year":"2015","journal-title":"Dev Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060373","article-title":"Phospholipid scramblase-3 regulates cardiolipin de novo biosynthesis and its resynthesis in growing HeLa cells","volume":"401","author":"Van","year":"2007","journal-title":"Biochem J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1042\/BST20260427","article-title":"Myoferlin at the crossroad of vesicle trafficking and mitochondrial function: implications for pancreatic cancer progression and stromal reprogramming","volume":"54","author":"Peiffer","year":"2026","journal-title":"Biochem Soc Trans"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2013-203728","article-title":"Systemic tryptophan and kynurenine catabolite levels relate to severity of rhinovirus-induced asthma exacerbation: a prospective study with a parallel-group design","volume":"68","author":"van der Sluijs","year":"2013","journal-title":"Thorax"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1898053\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:35:22Z","timestamp":1791524122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1898053\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2026.1898053"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1898053","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"article-number":"1898053"}}