{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:28:22Z","timestamp":1793413702595,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TropicalMed"],"abstract":"<jats:p>Dengue infection remains a major global health concern, with a subset of patients progressing from self-limited dengue fever to severe disease characterised by plasma leakage, shock, and organ dysfunction. The dengue non-structural protein 1 (NS1), a multifunctional glycoprotein expressed on infected cells and secreted into circulation, has emerged as a key mediator linking viral infection to immune-driven vascular pathology. This review synthesises experimental, animal, and human clinical evidence on NS1-driven immunopathogenesis, focusing on mechanisms leading to endothelial dysfunction and increased vascular permeability. NS1 modulates the complement system in a context-dependent manner, contributing to immune evasion by inhibiting terminal complement complex formation, while also promoting antibody-dependent complement activation associated with severe disease. Additionally, NS1 directly disrupts endothelial barrier integrity through disruption of adherens and tight junction architecture, Ang-2\/Tie2 imbalance, activation of RhoA\/ROCK (RhoA\/Rho-associated coiled-coil-containing protein kinase) signalling, and enzymatic degradation of the endothelial glycocalyx, with further amplification through inflammatory mediators. In addition, evidence shows that NS1 activates innate immune signalling, perturbs platelet biology and haemostasis, and forms pro-inflammatory complexes with lipoproteins. Moreover, anti-NS1 antibodies may be both protective and pathogenic. Collectively, these data position NS1-linked pathways as rational targets for adjunctive therapies and next-generation vaccines aimed at preventing vascular leakage and severe dengue infection.<\/jats:p>","DOI":"10.3390\/tropicalmed11050128","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:14:16Z","timestamp":1778530456000},"page":"128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dengue NS1 as a Driver of Immune-Mediated Pathogenesis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4682-8896","authenticated-orcid":false,"given":"Upeksha S.","family":"Wanigarathna","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 00300, Western Province, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1965-6678","authenticated-orcid":false,"given":"Senaka","family":"Rajapakse","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo 00700, Western Province, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisira L.","family":"Pathirana","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 00300, Western Province, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiroma M.","family":"Handunnetti","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 00300, Western Province, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-3176","authenticated-orcid":false,"given":"Andreas","family":"Nitsche","sequence":"additional","affiliation":[{"name":"Highly Pathogenic Viruses Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5899-9564","authenticated-orcid":false,"given":"Narmada","family":"Fernando","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 00300, Western Province, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1128\/CMR.11.3.480","article-title":"Dengue and dengue hemorrhagic fever","volume":"11","author":"Gubler","year":"1998","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/nrmicro2460","article-title":"Dengue: A continuing global threat","volume":"8","author":"Guzman","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Narvaez, F., Gutierrez, G., P\u00e9rez, M.A., Elizondo, D., Nu\u00f1ez, A., Balmaseda, A., and Harris, E. (2011). Evaluation of the traditional and revised WHO classifications of dengue disease severity. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001397"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120","DOI":"10.4103\/0974-2700.76835","article-title":"Dengue shock","volume":"4","author":"Rajapakse","year":"2011","journal-title":"J. Emerg. Trauma Shock"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rodrigo, C., Sigera, C., Fernando, D., and Rajapakse, S. (2021). Plasma leakage in dengue: A systematic review of prospective observational studies. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06793-2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13239-020-00485-9","article-title":"The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases","volume":"12","author":"Weinbaum","year":"2021","journal-title":"Cardiovasc. Eng. Technol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/500949","article-title":"Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement","volume":"193","author":"Avirutnan","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"424","DOI":"10.4049\/jimmunol.1100750","article-title":"Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation","volume":"187","author":"Avirutnan","year":"2011","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"304ra141","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":"Beatty","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"304ra142","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":"Modhiran","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chao, C.H., Wu, W.C., Lai, Y.C., Tsai, P.J., Perng, G.C., Lin, Y.S., and Yeh, T.-M. (2019). Dengue virus nonstructural protein 1 activates platelets via Toll-like receptor 4, leading to thrombocytopenia and hemorrhage. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007625"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9570","DOI":"10.1128\/JVI.00912-16","article-title":"Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins","volume":"90","author":"Conde","year":"2016","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.bbrc.2007.08.137","article-title":"Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1","volume":"362","author":"Kurosu","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","first-page":"992","article-title":"Association of Endothelial Glycocalyx and Tight and Adherens Junctions With Severity of Plasma Leakage in Dengue Infection","volume":"215","author":"Suwarto","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Puerta-Guardo, H., Biering, S.B., de Sousa, F.T.G., Shu, J., Glasner, D.R., Li, J., Blanc, S.F., Beatty, P.R., and Harris, E. (2022). Flavivirus NS1 Triggers Tissue-Specific Disassembly of Intercellular Junctions Leading to Barrier Dysfunction and Vascular Leak in a GSK-3\u03b2-Dependent Manner. Pathogens, 11.","DOI":"10.3390\/pathogens11060615"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1099\/jgv.0.001163","article-title":"Dengue virus or NS1 protein induces trans-endothelial cell permeability associated with VE-Cadherin and RhoA phosphorylation in HMEC-1 cells preventable by Angiopoietin-1","volume":"99","author":"Singh","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dom\u00ednguez-Alem\u00e1n, C.A., S\u00e1nchez-Vargas, L.A., Hern\u00e1ndez-Flores, K.G., Torres-Zugaide, A.I., Reyes-Sandoval, A., Cedillo-Barr\u00f3n, L., Remes-Ruiz, R., and Vivanco-Cid, H. (2021). Dengue Virus Induces the Expression and Release of Endocan from Endothelial Cells by an NS1\u2013TLR4-Dependent Mechanism. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061305"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pan, P., Li , G., Shen , M., Yu , Z., Ge , W., Lao , Z., Fan , Y., Chen , K., Ding , Z., and Wang , W. (2021). DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1008603"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1099\/jgv.0.001401","article-title":"Dengue virus non-structural protein 1 activates the p38 MAPK pathway to decrease barrier integrity in primary human endothelial cells","volume":"101","author":"Endy","year":"2020","journal-title":"J. Gen. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Avirutnan, P., Zhang, L., Punyadee, N., Manuyakorn, A., Puttikhunt, C., Kasinrerk, W., Malasit, P., Atkinson, J.P., and Diamond, M.S. (2007). Secreted NS1 of Dengue Virus Attaches to the Surface of Cells via Interactions with Heparan Sulfate and Chondroitin Sulfate E. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030183"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Puerta-Guardo, H., Glasner, D.R., and Harris, E. (2016). Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005738"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Glasner, D.R., Ratnasiri, K., Puerta-Guardo, H., Espinosa, D.A., Beatty, P.R., and Harris, E. (2017). Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006673"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1099\/jgv.0.001319","article-title":"Increased serum sialic acid is associated with morbidity and mortality in a murine model of dengue disease","volume":"100","author":"Espinosa","year":"2019","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Buijsers, B., Garishah, F.M., Riswari, S.F., van Ast, R.M., Pramudo, S.G., Tunjungputri, R.N., Overheul, G.J., van Rij, R.P., van der Ven, A., and Alisjahbana, B. (2021). Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.759570"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Chen, H.R., Chuang, Y.C., Lin, Y.S., Liu, H.S., Liu, C.C., Perng, G.C., and Yeh, T.-M. (2016). Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004828"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, H.R., Chao, C.H., Liu, C.C., Ho, T.S., Tsai, H.P., Perng, G.C., Lin, Y.-S., Wang, J.-R., and Yeh, T.-M. (2018). Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007033"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ebiom.2019.09.014","article-title":"High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity","volume":"48","author":"Lin","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e00258-20","DOI":"10.1128\/msphere.00258-20","article-title":"A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Nonstructural Protein 1","volume":"5","author":"Cheung","year":"2020","journal-title":"mSphere"},{"key":"ref_29","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":"Modhiran","year":"2017","journal-title":"Immunol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/cei.12747","article-title":"Dengue NS1 antigen contributes to disease severity by inducing interleukin (IL)-10 by monocytes","volume":"184","author":"Adikari","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","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":"Alayli","year":"2016","journal-title":"Virology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"EMBR202153600","DOI":"10.15252\/embr.202153600","article-title":"Dengue virus NS1 protein conveys pro-inflammatory signals by docking onto high-density lipoproteins","volume":"23","author":"Benfrid","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e01664-21","DOI":"10.1128\/jvi.01664-21","article-title":"Dengue Virus NS1 Uses Scavenger Receptor B1 as a Cell Receptor in Cultured Cells","volume":"96","author":"Maravillas","year":"2022","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1011587","DOI":"10.1371\/journal.ppat.1011587","article-title":"The dengue virus NS1 protein; new roles in pathogenesis due to similarities with and affinity for the high-density lipoprotein (HDL)?","volume":"19","author":"Ludert","year":"2023","journal-title":"PLoS Pathog."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e01974-20","DOI":"10.1128\/JVI.01974-20","article-title":"ApoA1 Neutralizes Proinflammatory Effects of Dengue Virus NS1 Protein and Modulates Viral Immune Evasion","volume":"95","author":"Coelho","year":"2021","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2056","DOI":"10.1002\/rmv.2056","article-title":"Serum lipid profile as a predictor of dengue severity: A systematic review and meta-analysis","volume":"29","author":"Lima","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_37","first-page":"e1226\u201334","article-title":"Dengue NS1 Antibodies Are Associated With Clearance of Viral Nonstructural Protein-1","volume":"230","author":"Sun","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"395","DOI":"10.4049\/jimmunol.174.1.395","article-title":"Expression of Cytokine, Chemokine, and Adhesion Molecules during Endothelial Cell Activation Induced by Antibodies against Dengue Virus Nonstructural Protein 1","volume":"174","author":"Lin","year":"2005","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.4049\/jimmunol.1500136","article-title":"Endothelial Cell Sensitisation by Death Receptor Fractions of an Anti\u2013Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice","volume":"195","author":"Sun","year":"2015","journal-title":"J. Immunol."},{"key":"ref_40","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":"Sun","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_41","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":"Wan","year":"2016","journal-title":"Thromb. Haemost."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5242","DOI":"10.1038\/s41467-018-07667-z","article-title":"Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection","volume":"9","author":"Jayathilaka","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1093\/infdis\/jiae137","article-title":"Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus Through Antibody-Dependent Cellular Cytotoxicity","volume":"230","author":"Mathew","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lebeau, G., Lagrave, A., Ogire, E., Grondin, L., Seriacaroupin, S., Moutoussamy, C., Mavingui, P., Hoarau, J.-J., Roche, M., and Krejbich-Trotot, P. (2021). Viral toxin NS1 implication in dengue pathogenesis making it a pivotal target in development of efficient vaccine. Vaccines, 9.","DOI":"10.20944\/preprints202106.0228.v1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41541-025-01366-9","article-title":"The TAK-003 story: Key decisions that shaped development of a tetravalent dengue vaccine","volume":"11","author":"Escudero","year":"2026","journal-title":"npj Vaccines"}],"container-title":["Tropical Medicine and Infectious Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2414-6366\/11\/5\/128\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:45:51Z","timestamp":1778532351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2414-6366\/11\/5\/128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":45,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["tropicalmed11050128"],"URL":"https:\/\/doi.org\/10.3390\/tropicalmed11050128","relation":{},"ISSN":["2414-6366"],"issn-type":[{"value":"2414-6366","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}