{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:57:09Z","timestamp":1787021829160,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013928","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000}}],"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["No. 2023YFC2506000"],"award-info":[{"award-number":["No. 2023YFC2506000"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever with high mortality, primarily driven by immune dysregulation. This study aimed to characterize the expression profile of TIM-3 expression on peripheral NK cells in SFTS, explore the role of TIM-3\u2009\u207a\u2009NK cells in disease progression, and evaluate soluble TIM-3 (sTIM-3) and Galectin-9 (sGalectin-9) as prognostic biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public single-cell RNA sequencing (scRNA-seq) datasets were analyzed using weighted gene co-expression network analysis (WGCNA). Peripheral blood samples from 21 SFTS patients and 14 healthy donors collected at the First Affiliated Hospital, Zhejiang University School of Medicine, were analyzed by flow cytometry, functional assays, and serological assessments. NK cell cytotoxicity was assessed by granzyme B, perforin, IFN-\u03b3, and TNF-\u03b1 production. Serum sTIM-3 and sGalectin-9 were measured by Cytometric Bead Array.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TIM-3\u2009\u207a\u2009NK cells were significantly increased in SFTS patients, especially in fatal cases. WGCNA identified\n                      <jats:italic>HAVCR2<\/jats:italic>\n                      (encoding TIM-3) as a mortality-associated hub gene. TIM-3\u2009\u207a\u2009NK cells exhibited enhanced granzyme B and perforin expression, while TIM-3 blockade significantly reduced IFN-\u03b3 and TNF-\u03b1 production. Elevated sTIM-3 and sGalectin-9 levels were correlated with fatal outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Activated TIM-3\u2009\u207a\u2009NK cells were associated with fatal outcomes in SFTS. TIM-3\u2009\u207a\u2009NK cell proportion, sTIM-3, and sGalectin-9 may serve as novel prognostic biomarkers and therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0013928","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:54:31Z","timestamp":1768589671000},"page":"e0013928","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Immune checkpoint TIM-3 defines hyperactivated NK cells and predicts fatal outcome in severe fever with thrombocytopenia syndrome"],"prefix":"10.1371","volume":"20","author":[{"given":"Xiaohan","family":"Qian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziling","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolin","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingtong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2892-5956","authenticated-orcid":true,"given":"Wei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"issue":"12","key":"pntd.0013928.ref001","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1007\/s00705-020-04731-2","article-title":"2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales","volume":"165","author":"JH Kuhn","year":"2020","journal-title":"Arch Virol"},{"issue":"16","key":"pntd.0013928.ref002","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1056\/NEJMoa1010095","article-title":"Fever with thrombocytopenia associated with a novel bunyavirus in China","volume":"364","author":"X-J Yu","year":"2011","journal-title":"N Engl J Med"},{"issue":"8","key":"pntd.0013928.ref003","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S1473-3099(14)70718-2","article-title":"Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis","volume":"14","author":"Q Liu","year":"2014","journal-title":"Lancet Infect Dis"},{"issue":"8","key":"pntd.0013928.ref004","doi-asserted-by":"crossref","first-page":"110039","DOI":"10.1016\/j.celrep.2021.110039","article-title":"Single-cell landscape of peripheral immune responses to fatal SFTS","volume":"37","author":"H Li","year":"2021","journal-title":"Cell Rep"},{"issue":"10","key":"pntd.0013928.ref005","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S1473-3099(18)30293-7","article-title":"Epidemiological and clinical features of laboratory-diagnosed severe fever with thrombocytopenia syndrome in China, 2011-17: a prospective observational study","volume":"18","author":"H Li","year":"2018","journal-title":"Lancet Infect Dis"},{"issue":"2","key":"pntd.0013928.ref006","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1172\/JCI134512","article-title":"Identifying target cells for a tick-borne virus that causes fatal hemorrhagic fever","volume":"130","author":"S Yamaoka","year":"2020","journal-title":"J Clin Invest"},{"issue":"7","key":"pntd.0013928.ref007","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1093\/infdis\/jis452","article-title":"Host cytokine storm is associated with disease severity of severe fever with thrombocytopenia syndrome","volume":"206","author":"Y Sun","year":"2012","journal-title":"J Infect Dis"},{"issue":"1","key":"pntd.0013928.ref008","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41598-017-18616-z","article-title":"The Regulation of Seventeen Inflammatory Mediators are Associated with Patient Outcomes in Severe Fever with Thrombocytopenia Syndrome","volume":"8","author":"L-F Hu","year":"2018","journal-title":"Sci Rep"},{"issue":"1","key":"pntd.0013928.ref009","doi-asserted-by":"crossref","first-page":"106181","DOI":"10.1016\/j.jinf.2024.106181","article-title":"Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial","volume":"89","author":"H-H Ge","year":"2024","journal-title":"J Infect"},{"issue":"459","key":"pntd.0013928.ref010","article-title":"Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome","volume":"10","author":"X-K Li","year":"2018","journal-title":"Sci Transl Med"},{"issue":"1","key":"pntd.0013928.ref011","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.1038\/s41467-018-05746-9","article-title":"Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection","volume":"9","author":"P Song","year":"2018","journal-title":"Nat Commun"},{"issue":"2","key":"pntd.0013928.ref012","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1172\/JCI129171","article-title":"Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections","volume":"130","author":"T Suzuki","year":"2020","journal-title":"J Clin Invest"},{"key":"pntd.0013928.ref013","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1146\/annurev-immunol-082619-124440","article-title":"Mechanisms of Natural Killer Cell Evasion Through Viral Adaptation","volume":"38","author":"M Mancini","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"pntd.0013928.ref014","doi-asserted-by":"crossref","first-page":"1508423","DOI":"10.3389\/fmicb.2024.1508423","article-title":"Can there be calm during a cytokine storm? Immune checkpoint pathways affecting the severity of COVID-19 disease","volume":"15","author":"M Meggyes","year":"2024","journal-title":"Front Microbiol"},{"issue":"6871","key":"pntd.0013928.ref015","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/415536a","article-title":"Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease","volume":"415","author":"L Monney","year":"2002","journal-title":"Nature"},{"issue":"3","key":"pntd.0013928.ref016","article-title":"TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action","volume":"18","author":"W Du","year":"2017","journal-title":"Int J Mol Sci"},{"issue":"16","key":"pntd.0013928.ref017","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1182\/blood-2011-11-392951","article-title":"Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity","volume":"119","author":"LC Ndhlovu","year":"2012","journal-title":"Blood"},{"issue":"2","key":"pntd.0013928.ref018","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cyto.2015.05.012","article-title":"Tim-3 pathway affects NK cell impairment in patients with active tuberculosis","volume":"76","author":"F Wang","year":"2015","journal-title":"Cytokine"},{"issue":"2","key":"pntd.0013928.ref019","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.intimp.2015.09.017","article-title":"Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma","volume":"29","author":"L Xu","year":"2015","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pntd.0013928.ref020","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-010618","article-title":"Differential impact of TIM-3 ligands on NK cell function","volume":"13","author":"J Wang","year":"2025","journal-title":"J Immunother Cancer"},{"issue":"5","key":"pntd.0013928.ref021","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s12250-020-00224-3","article-title":"Depletion but Activation of CD56dimCD16+\u2009NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus","volume":"35","author":"M Li","year":"2020","journal-title":"Virol Sin"},{"issue":"4","key":"pntd.0013928.ref022","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10238-013-0259-0","article-title":"Detection and evaluation of immunofunction of patients with severe fever with thrombocytopenia syndrome","volume":"14","author":"L Sun","year":"2014","journal-title":"Clin Exp Med"},{"issue":"1","key":"pntd.0013928.ref023","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13073-023-01249-5","article-title":"Annotation of cell types (ACT): a convenient web server for cell type annotation","volume":"15","author":"F Quan","year":"2023","journal-title":"Genome Med"},{"issue":"19","key":"pntd.0013928.ref024","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2023.07.034","article-title":"A pan-cancer single-cell panorama of human natural killer cells","volume":"186","author":"F Tang","year":"2023","journal-title":"Cell"},{"issue":"5","key":"pntd.0013928.ref025","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"issue":"1","key":"pntd.0013928.ref026","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"S Jin","year":"2021","journal-title":"Nat Commun"},{"issue":"3","key":"pntd.0013928.ref027","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nmeth.4150","article-title":"Single-cell mRNA quantification and differential analysis with Census","volume":"14","author":"X Qiu","year":"2017","journal-title":"Nat Methods"},{"issue":"12","key":"pntd.0013928.ref028","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/s41587-020-0591-3","article-title":"Generalizing RNA velocity to transient cell states through dynamical modeling","volume":"38","author":"V Bergen","year":"2020","journal-title":"Nat Biotechnol"},{"key":"pntd.0013928.ref029","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"11","key":"pntd.0013928.ref030","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Res"},{"key":"pntd.0013928.ref031","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1471-2105-4-2","article-title":"An automated method for finding molecular complexes in large protein interaction networks","volume":"4","author":"GD Bader","year":"2003","journal-title":"BMC Bioinformatics"},{"key":"pntd.0013928.ref032","article-title":"cytoHubba: identifying hub objects and sub-networks from complex interactome","volume":"8","author":"C-H Chin","year":"2014","journal-title":"BMC Syst Biol"},{"issue":"8","key":"pntd.0013928.ref033","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1038\/s41590-024-01883-0","article-title":"High-dimensional single-cell analysis of human natural killer cell heterogeneity","volume":"25","author":"L Rebuffet","year":"2024","journal-title":"Nat Immunol"},{"key":"pntd.0013928.ref034","doi-asserted-by":"crossref","first-page":"104807","DOI":"10.1016\/j.ebiom.2023.104807","article-title":"Clinical efficacy of immunoglobulin on the treatment of severe fever with thrombocytopenia syndrome: a retrospective cohort study","volume":"96","author":"S-S Zhang","year":"2023","journal-title":"EBioMedicine"},{"key":"pntd.0013928.ref035","doi-asserted-by":"crossref","first-page":"1123155","DOI":"10.3389\/fimmu.2023.1123155","article-title":"SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis","volume":"14","author":"M Lenart","year":"2023","journal-title":"Front Immunol"},{"issue":"1","key":"pntd.0013928.ref036","doi-asserted-by":"crossref","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":"A Park","year":"2021","journal-title":"mBio"},{"issue":"1","key":"pntd.0013928.ref037","doi-asserted-by":"crossref","DOI":"10.1016\/j.immuni.2023.11.018","article-title":"Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection","volume":"57","author":"T Torcellan","year":"2024","journal-title":"Immunity"},{"key":"pntd.0013928.ref038","doi-asserted-by":"crossref","first-page":"1267774","DOI":"10.3389\/fimmu.2023.1267774","article-title":"NK cell subsets and dysfunction during viral infection: a new avenue for therapeutics?","volume":"14","author":"JC Bjorgen","year":"2023","journal-title":"Front Immunol"},{"issue":"1","key":"pntd.0013928.ref039","doi-asserted-by":"crossref","first-page":"1889822","DOI":"10.1080\/2162402X.2021.1889822","article-title":"TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients","volume":"10","author":"J Rakova","year":"2021","journal-title":"Oncoimmunology"},{"issue":"13","key":"pntd.0013928.ref040","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1182\/blood-2011-06-360321","article-title":"Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9","volume":"119","author":"MK Gleason","year":"2012","journal-title":"Blood"},{"issue":"3","key":"pntd.0013928.ref041","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.imbio.2019.03.001","article-title":"NK cell expression of Tim-3: First impressions matter","volume":"224","author":"EC So","year":"2019","journal-title":"Immunobiology"},{"key":"pntd.0013928.ref042","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.intimp.2018.09.016","article-title":"Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer","volume":"64","author":"M Yin","year":"2018","journal-title":"Int Immunopharmacol"},{"issue":"3","key":"pntd.0013928.ref043","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s44321-024-00026-0","article-title":"Inhibition of SFTSV replication in humanized mice by a subcutaneously administered anti-PD1 nanobody","volume":"16","author":"M Ji","year":"2024","journal-title":"EMBO Mol Med"},{"issue":"1","key":"pntd.0013928.ref044","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/s12916-024-03421-z","article-title":"Ruxolitinib plus standard of care in severe hospitalized adults with severe fever with thrombocytopenia syndrome (SFTS): an exploratory, single-arm trial","volume":"22","author":"S Wen","year":"2024","journal-title":"BMC Med"},{"issue":"1","key":"pntd.0013928.ref045","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12985-024-02403-0","article-title":"Cytokines and lymphocyte subsets are associated with disease severity of severe fever with thrombocytopenia syndrome","volume":"21","author":"L Song","year":"2024","journal-title":"Virol J"},{"key":"pntd.0013928.ref046","article-title":"Development and validation of a novel mortality risk stratification simplified scoring scale for severe fever with thrombocytopenia syndrome","author":"T Chen","year":"2025","journal-title":"Clin Microbiol Infect"},{"issue":"1","key":"pntd.0013928.ref047","doi-asserted-by":"crossref","first-page":"2498572","DOI":"10.1080\/22221751.2025.2498572","article-title":"A machine learning model for mortality prediction in patients with severe fever with thrombocytopenia syndrome: a prospective, multicenter cohort study","volume":"14","author":"Y Liu","year":"2025","journal-title":"Emerg Microbes Infect"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0013928","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013928","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T19:05:28Z","timestamp":1769195128000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013928"}},"subtitle":[],"editor":[{"given":"Nam-Hyuk","family":"Cho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0013928","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]}}}