{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:10:33Z","timestamp":1791850233168,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1007625","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T00:00:00Z","timestamp":1555891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2321-B-006-011"],"award-info":[{"award-number":["MOST 107-2321-B-006-011"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["NHRI-108A1-MRCO-0319191"],"award-info":[{"award-number":["NHRI-108A1-MRCO-0319191"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"DOI":"10.1371\/journal.ppat.1007625","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T13:36:23Z","timestamp":1555940183000},"page":"e1007625","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":182,"title":["Dengue virus nonstructural protein 1 activates platelets via Toll-like receptor 4, leading to thrombocytopenia and hemorrhage"],"prefix":"10.1371","volume":"15","author":[{"given":"Chiao-Hsuan","family":"Chao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chueh","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Chung","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Jane","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guey-Chuen","family":"Perng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee-Shin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3172-7432","authenticated-orcid":true,"given":"Trai-Ming","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2019,4,22]]},"reference":[{"issue":"12 Suppl","key":"ref1","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/nrmicro2460","article-title":"Dengue: a continuing global threat","volume":"8","author":"MG Guzman","year":"2010","journal-title":"Nat Rev Microbiol"},{"issue":"7446","key":"ref2","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"S Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref3","unstructured":"WorldHealthOrganization. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. WHO Guidelines Approved by the Guidelines Review Committee. 2009."},{"key":"ref4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12929-015-0191-6","article-title":"Biomarkers of severe dengue disease\u2014a review","volume":"22","author":"DV John","year":"2015","journal-title":"J Biomed Sci"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1186\/s12879-014-0570-8","article-title":"Dengue NS1 antigen as a marker of severe clinical disease","volume":"14","author":"SA Paranavitane","year":"2014","journal-title":"BMC Infect Dis"},{"issue":"6","key":"ref6","doi-asserted-by":"crossref","first-page":"e0004804","DOI":"10.1371\/journal.pntd.0004804","article-title":"HMGB1 Is a Potential Biomarker for Severe Viral Hemorrhagic Fevers","volume":"10","author":"K Resman Rus","year":"2016","journal-title":"PLoS Neglect Trop D"},{"issue":"2","key":"ref7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.4269\/ajtmh.2012.11-0469","article-title":"A three-component biomarker panel for prediction of dengue hemorrhagic fever","volume":"86","author":"AR Brasier","year":"2012","journal-title":"Am J Trop Med Hyg"},{"issue":"4","key":"ref8","doi-asserted-by":"crossref","first-page":"e0005498","DOI":"10.1371\/journal.pntd.0005498","article-title":"The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue","volume":"11","author":"PK Lam","year":"2017","journal-title":"PLoS Neglect Trop D"},{"issue":"5","key":"ref9","doi-asserted-by":"crossref","first-page":"e1006385","DOI":"10.1371\/journal.ppat.1006385","article-title":"Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue","volume":"13","author":"MRO Trugilho","year":"2017","journal-title":"PLoS Pathog"},{"issue":"5","key":"ref10","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/jth.12178","article-title":"Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases","volume":"11","author":"ED Hottz","year":"2013","journal-title":"J Thromb Haemost"},{"issue":"2","key":"ref11","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.antiviral.2013.03.008","article-title":"The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker","volume":"98","author":"DA Muller","year":"2013","journal-title":"Antiviral Res"},{"issue":"2","key":"ref12","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1128\/JCM.40.02.376-381.2002","article-title":"Enzyme-linked immunosorbent assay specific to Dengue virus type 1 nonstructural protein NS1 reveals circulation of the antigen in the blood during the acute phase of disease in patients experiencing primary or secondary infections","volume":"40","author":"S Alcon","year":"2002","journal-title":"J Clin Microbiol"},{"issue":"9","key":"ref13","doi-asserted-by":"crossref","first-page":"16087","DOI":"10.1038\/nmicrobiol.2016.87","article-title":"Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes","volume":"1","author":"J Liu","year":"2016","journal-title":"Nat Microbiol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.virol.2016.06.008","article-title":"Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells","volume":"496","author":"F Alayli","year":"2016","journal-title":"Virology"},{"issue":"304","key":"ref15","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"N Modhiran","year":"2015","journal-title":"Sci Transl Med"},{"issue":"304","key":"ref16","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaa3787","article-title":"Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination","volume":"7","author":"PR Beatty","year":"2015","journal-title":"Sci Transl Med"},{"issue":"7","key":"ref17","doi-asserted-by":"crossref","first-page":"e0004828","DOI":"10.1371\/journal.pntd.0004828","article-title":"Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy","volume":"10","author":"HR Chen","year":"2016","journal-title":"PLoS Neglect Trop D"},{"issue":"11","key":"ref18","doi-asserted-by":"crossref","first-page":"e1006673","DOI":"10.1371\/journal.ppat.1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components","volume":"13","author":"DR Glasner","year":"2017","journal-title":"PLoS Pathog"},{"issue":"6","key":"ref19","doi-asserted-by":"crossref","first-page":"e65900","DOI":"10.1371\/journal.pone.0065900","article-title":"Dengue in travelers: kinetics of viremia and NS1 antigenemia and their associations with clinical parameters","volume":"8","author":"EO Erra","year":"2013","journal-title":"PloS One"},{"issue":"5","key":"ref20","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/icb.2017.5","article-title":"Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6","volume":"95","author":"N Modhiran","year":"2017","journal-title":"Immunol Cell Biol"},{"issue":"12","key":"ref21","doi-asserted-by":"crossref","first-page":"7997","DOI":"10.4049\/jimmunol.0802884","article-title":"Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4\/MyD88 and the cGMP-dependent protein kinase pathway","volume":"182","author":"G Zhang","year":"2009","journal-title":"J Immunol"},{"issue":"1","key":"ref22","doi-asserted-by":"crossref","first-page":"6975","DOI":"10.1038\/s41598-017-07308-3","article-title":"Antibodies Against Modified NS1 Wing Domain Peptide Protect Against Dengue Virus Infection","volume":"7","author":"YC Lai","year":"2017","journal-title":"Sci Rep"},{"issue":"4","key":"ref23","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1074\/jbc.274.4.1898","article-title":"Fc receptor-mediated platelet activation is dependent on phosphatidylinositol 3-kinase activation and involves p120(Cbl)","volume":"274","author":"A Saci","year":"1999","journal-title":"J Biol Chem"},{"issue":"7","key":"ref24","doi-asserted-by":"crossref","first-page":"e1005053","DOI":"10.1371\/journal.ppat.1005053","article-title":"Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection","volume":"11","author":"J Chen","year":"2015","journal-title":"PLoS Pathog"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.thromres.2017.07.031","article-title":"Platelet Toll-like receptor (TLR) expression and TLR-mediated platelet activation in acute myocardial infarction","volume":"158","author":"KE Hally","year":"2017","journal-title":"Thromb Res"},{"issue":"8","key":"ref26","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1182\/blood.V94.8.2725.420k18_2725_2734","article-title":"Circulating activated platelets assist THP-1 monocytoid\/endothelial cell interaction under shear stress","volume":"94","author":"G Theilmeier","year":"1999","journal-title":"Blood"},{"issue":"2","key":"ref27","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1189\/jlb.0708400","article-title":"Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases","volume":"85","author":"JM van Gils","year":"2009","journal-title":"J Leukoc Biol"},{"issue":"21","key":"ref28","doi-asserted-by":"crossref","first-page":"5254","DOI":"10.1182\/blood-2008-09-180794","article-title":"Neutrophils phagocytose activated platelets in vivo: a phosphatidylserine, P-selectin, and beta2 integrin-dependent cell clearance program","volume":"113","author":"N Maugeri","year":"2009","journal-title":"Blood"},{"issue":"1","key":"ref29","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s00011-007-6115-5","article-title":"Optimized THP-1 differentiation is required for the detection of responses to weak stimuli","volume":"56","author":"EK Park","year":"2007","journal-title":"Inflamm Res"},{"issue":"11","key":"ref30","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1128\/JVI.02575-06","article-title":"Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage","volume":"81","author":"HC Chen","year":"2007","journal-title":"J Virol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"41697","DOI":"10.1038\/srep41697","article-title":"Platelet activation determines the severity of thrombocytopenia in dengue infection","volume":"7","author":"A Ojha","year":"2017","journal-title":"Sci Rep"},{"issue":"2","key":"ref32","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1182\/blood-2005-06-2202","article-title":"Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo","volume":"107","author":"R Aslam","year":"2006","journal-title":"Blood"},{"issue":"7","key":"ref33","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1182\/blood-2005-03-0916","article-title":"Platelets express functional Toll-like receptor-4","volume":"106","author":"G Andonegui","year":"2005","journal-title":"Blood"},{"key":"ref34","first-page":"313842","article-title":"Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators","volume":"2015","author":"EL de Azeredo","year":"2015","journal-title":"Mediat Inflamm"},{"issue":"21","key":"ref35","doi-asserted-by":"crossref","first-page":"11648","DOI":"10.1128\/JVI.01156-13","article-title":"Inhibition of megakaryocyte development in the bone marrow underlies dengue virus-induced thrombocytopenia in humanized mice","volume":"87","author":"A Sridharan","year":"2013","journal-title":"J Virol"},{"issue":"3","key":"ref36","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1159\/000135658","article-title":"Increased values of mean platelet volume and platelet size deviation width may provide a safe positive diagnosis of idiopathic thrombocytopenic purpura","volume":"119","author":"G Ntaios","year":"2008","journal-title":"Acta haematologica"},{"issue":"11","key":"ref37","first-page":"Ec01","article-title":"Association of Mean Platelet Volume with Severity, Serology & Treatment Outcome in Dengue Fever: Prognostic Utility","volume":"9","author":"K Sharma","year":"2015","journal-title":"J Clin Diagn Res"},{"issue":"3","key":"ref38","first-page":"611","article-title":"Use of mean platelet volume and platelet distribution width in predicting trend in platelet count and bleeding risks in patients of dengue fever","volume":"3","author":"GM Parakash","year":"2016","journal-title":"Int J Adv Med"},{"issue":"12","key":"ref39","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1128\/JCM.00707-17","article-title":"Progress and Challenges towards Point-of-Care Diagnostic Development for Dengue","volume":"55","author":"J Pang","year":"2017","journal-title":"J Clin Microbiol"},{"issue":"11","key":"ref40","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1111\/j.1538-7836.2007.02754.x","article-title":"Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice","volume":"5","author":"DS Sun","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"5","key":"ref41","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1160\/TH14-07-0637","article-title":"Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcgammaRIII","volume":"113","author":"TS Lien","year":"2015","journal-title":"Thromb Haemost"},{"issue":"3","key":"ref42","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1160\/th15-06-0498","article-title":"Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages","volume":"115","author":"SW Wan","year":"2016","journal-title":"Thromb Haemost"},{"issue":"6","key":"ref43","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1136\/ebmed-2017-110745","article-title":"Prophylactic platelet transfusion does not reduce risk of clinical bleeding in adults with dengue and thrombocytopaenia","volume":"22","author":"MZ Khan Assir","year":"2017","journal-title":"Evid Based Med"},{"issue":"5","key":"ref44","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/nsmb.3213","article-title":"Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses","volume":"23","author":"H Song","year":"2016","journal-title":"Nat Struct Mol Biol"},{"key":"ref45","article-title":"The Good, the Bad, and the Shocking: The Multiple Roles of Dengue Virus Nonstructural Protein 1 in Protection and Pathogenesis","author":"DR Glasner","year":"2018","journal-title":"Annu Rev Virol"},{"issue":"304","key":"ref46","doi-asserted-by":"crossref","first-page":"304fs37","DOI":"10.1126\/scitranslmed.aad1255","article-title":"NS1: A corner piece in the dengue pathogenesis puzzle?","volume":"7","author":"SJ Thomas","year":"2015","journal-title":"Sci Transl Med"},{"issue":"4","key":"ref47","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.4049\/jimmunol.1400091","article-title":"Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue","volume":"193","author":"ED Hottz","year":"2014","journal-title":"J Immunol"},{"issue":"20","key":"ref48","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1182\/blood-2013-05-504449","article-title":"Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation","volume":"122","author":"ED Hottz","year":"2013","journal-title":"Blood"},{"issue":"1","key":"ref49","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12929-018-0462-0","article-title":"Dengue virus non-structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate","volume":"25","author":"HR Chen","year":"2018","journal-title":"J Biomed Sci"},{"issue":"4","key":"ref50","doi-asserted-by":"crossref","first-page":"e1007033","DOI":"10.1371\/journal.ppat.1007033","article-title":"Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability","volume":"14","author":"HR Chen","year":"2018","journal-title":"PLoS Pathog"},{"issue":"5","key":"ref51","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jinf.2009.02.018","article-title":"Dengue virus induces thrombomodulin expression in human endothelial cells and monocytes in vitro","volume":"58","author":"LC Chen","year":"2009","journal-title":"J infect"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1007625","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.ppat.1007625","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T16:23:51Z","timestamp":1588955031000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1007625"}},"subtitle":[],"editor":[{"given":"Richard J.","family":"Kuhn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2019,4,22]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1007625","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,22]]}}}