{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:30:26Z","timestamp":1790857826879,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Oxford Glycobiology endowment"},{"name":"Commonwealth Scholarship Commission"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Infections caused by dengue virus (DENV) result in significant morbidity and mortality. A proportion of infected individuals develop dengue haemorrhagic fever (DHF) characterized by circulatory collapse and multiorgan failure. Early detection of individuals likely to develop DHF could lead to improved outcomes for patients and help us use healthcare resources more efficiently. We identified proteins that are differentially regulated during early disease in peripheral blood mononuclear cells (PBMCs) of patients who subsequently developed DHF. Four dengue fever (DF), four DHF and two healthy control PBMCs were subjected to tandem mass tag mass spectrometry. Differentially regulated proteins were used to identify up- or down-regulated Gene Ontology pathways. One hundred and sixty proteins were differentially expressed in DENV-infected samples compared to healthy controls. PBMCs from DHF patients differentially expressed 90 proteins compared to DF; these were involved in down-regulation of platelet activation and aggregation, cell adhesion, and cytoskeleton arrangement pathways. Proteins involved in oxidative stress and p38 MAPK signalling were upregulated in DHF samples during early infection compared to DF. This study has identified 90 proteins differentially regulated in PBMCs that could potentially serve as biomarkers to identify patients at risk of developing DHF at an early disease stage.<\/jats:p>","DOI":"10.3390\/v17060805","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T12:27:09Z","timestamp":1748867229000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomics Analysis of Peripheral Blood Mononuclear Cells from Patients in Early Dengue Infection Reveals Potential Markers of Subsequent Fluid Leakage"],"prefix":"10.3390","volume":"17","author":[{"given":"Nilanka","family":"Perera","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"},{"name":"Department of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-5291","authenticated-orcid":false,"given":"Abhinav","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7466-2977","authenticated-orcid":false,"given":"Bevin","family":"Gangadharan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-8908","authenticated-orcid":false,"given":"Diyanath","family":"Ranasinghe","sequence":"additional","affiliation":[{"name":"Department of Immunology and Molecular Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-1813","authenticated-orcid":false,"given":"Ananda","family":"Wijewickrama","sequence":"additional","affiliation":[{"name":"National Institute of Infectious Diseases, Angoda 10620, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gathsaurie Neelika","family":"Malavige","sequence":"additional","affiliation":[{"name":"Department of Immunology and Molecular Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4383-4641","authenticated-orcid":false,"given":"Joanna L.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-4949","authenticated-orcid":false,"given":"Nicole","family":"Zitzmann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford OX1 3QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.4269\/ajtmh.2011.10-0521","article-title":"Health economics of dengue: A systematic literature review and expert panel\u2019s assessment","volume":"84","author":"Beatty","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_3","unstructured":"World Health Organization (2023, February 12). Dengue and Severe Dengue. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2149\/tmh.2011-S10","article-title":"Clinical manifestations and management of dengue\/DHF\/DSS","volume":"39","author":"Kalayanarooj","year":"2011","journal-title":"Trop. Med. Health"},{"key":"ref_5","unstructured":"World Health Organization (2011). Regional Office for South-East Asia. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever, World Health Organization."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.jiph.2023.08.001","article-title":"Dengue overview: An updated systemic review","volume":"16","author":"Khan","year":"2023","journal-title":"J. Infect. Public health"},{"key":"ref_7","unstructured":"World Health Organization (2023, April 14). Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789241547871."},{"key":"ref_8","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_9","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_10","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_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00284-020-02284-w","article-title":"Current Understanding of the Pathogenesis of Dengue Virus Infection","volume":"78","author":"Bhatt","year":"2021","journal-title":"Curr. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sekaran, S.D., Ismail, A.A., Thergarajan, G., Chandramathi, S., Rahman, S.K.H., Mani, R.R., Jusof, F.F., Lim, Y.A.L., and Manikam, R. (2022). Host immune response against DENV and ZIKV infections. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.975222"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eade7702","DOI":"10.1126\/sciadv.ade7702","article-title":"Magnitude and Kinetics of the Human Immune Cell Response Associated with Severe Dengue Progression by Single-Cell Proteomics","volume":"9","author":"Robinson","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fernandes-Santos, C., and de Azeredo, E.L. (2022). Innate Immune Response to Dengue Virus: Toll-like Receptors and Antiviral Response. Viruses, 14.","DOI":"10.3390\/v14050992"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"King, C.A., Wegman, A.D., and Endy, T.P. (2020). Mobilization and Activation of the Innate Immune Response to Dengue Virus. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.574417"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.trsl.2017.06.007","article-title":"RNA-Seq analysis of peripheral blood mononuclear cells reveals unique transcriptional signatures associated with disease progression in dengue patients","volume":"186","author":"Banerjee","year":"2017","journal-title":"Transl. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Popper, S.J., Gordon, A., Liu, M., Balmaseda, A., Harris, E., and Relman, D.A. (2012). Temporal Dynamics of the Transcriptional Response to Dengue Virus Infection in Nicaraguan Children. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001966"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12982","DOI":"10.1128\/JVI.01224-10","article-title":"The Early Whole-Blood Transcriptional Signature of Dengue Virus and Features Associated with Progression to Dengue Shock Syndrome in Vietnamese Children and Young Adults","volume":"84","author":"Hoang","year":"2010","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1089\/omi.2017.0135","article-title":"Clinical Proteomics and Cytokine Profiling for Dengue Fever Disease Severity Biomarkers","volume":"21","author":"Jadhav","year":"2017","journal-title":"OMICS"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fragnoud, R., Flamand, M., Reynier, F., Buchy, P., Duong, V., Pachot, A., Paranhos-Baccala, G., and Bedin, F. (2015). Differential proteomic analysis of virus-enriched fractions obtained from plasma pools of patients with dengue fever or severe dengue. BMC Infect. Dis., 15.","DOI":"10.1186\/s12879-015-1271-7"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1111\/tmi.12931","article-title":"Proteomic analysis reveals the enhancement of human serum apolipoprotein A-1(APO A-1) in individuals infected with multiple dengue virus serotypes","volume":"22","author":"Manchala","year":"2017","journal-title":"Trop. Med. Int. Health"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Han, L., Ao, X., Lin, S., Guan, S., Zheng, L., Han, X., and Ye, H. (2019). Quantitative Comparative Proteomics Reveal Biomarkers for Dengue Disease Severity. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.02836"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12014-024-09477-6","article-title":"Neat plasma proteomics: Getting the best out of the worst","volume":"21","author":"Metatla","year":"2024","journal-title":"Clin. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Fabregat","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1093\/infdis\/jiy086","article-title":"A blood RNA signature detecting severe disease in young dengue patients at hospital arrival","volume":"217","author":"Nikolayeva","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1089\/vim.2022.0160","article-title":"Differential Expression Patterns of Indoleamine 2,3-Dioxygenase 1 and Other Tryptophan and Arginine Catabolic Pathway Genes in Dengue Correlate with Clinical Severity-Pilot Study Results","volume":"36","author":"Jose","year":"2023","journal-title":"Viral Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hapugaswatta, H., Amarasena, P., Premaratna, R., Seneviratne, K.N., and Jayathilaka, N. (2020). Differential expression of microRNA, miR-150 and enhancer of zeste homolog 2 (EZH2) in peripheral blood cells as early prognostic markers of severe forms of dengue. J. Biomed. Sci., 27.","DOI":"10.1186\/s12929-020-0620-z"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.celrep.2019.01.033","article-title":"A 20-Gene Set Predictive of Progression to Severe Dengue","volume":"26","author":"Robinson","year":"2019","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Trugilho, M.R.d.O., Hottz, E.D., Brunoro, G.V.F., Teixeira-Ferreira, A., Carvalho, P.C., Salazar, G.A., Zimmerman, G.A., Bozza, F.A., Bozza, P.T., and Perales, J. (2017). Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006385"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mirzalieva, O., Juncker, M., Schwartzenburg, J., and Desai, S. (2022). ISG15 and ISGylation in Human Diseases. Cells, 11.","DOI":"10.3390\/cells11030538"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s12250-019-00086-4","article-title":"The Role of Host Cytoskeleton in Flavivirus Infection","volume":"34","author":"Zhang","year":"2019","journal-title":"Virol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Suttitheptumrong, A., Mahutchariyakul, T., Rawarak, N., Reamtong, O., Boonnak, K., and Pattanakitsakul, S.-N. (2021). Altered moesin and actin cytoskeleton protein rearrangements affect transendothelial permeability in human endothelial cells upon dengue virus infection and TNF-\u03b1 treatment. Viruses, 13.","DOI":"10.3390\/v13102042"},{"key":"ref_35","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":"Brasier","year":"2012","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1084\/jem.20071800","article-title":"Talin is required for integrin-mediated platelet function in hemostasis and thrombosis","volume":"204","author":"Petrich","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"De Silva, E., Hong, F., Falet, H., and Kim, H. (2022). Filamin A in platelets: Bridging the (signaling) gap between the plasma membrane and the actin cytoskeleton. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.1060361"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1161\/ATVBAHA.122.318179","article-title":"Regulation of VWF (Von Willebrand Factor) in Inflammatory Thrombosis","volume":"42","author":"Manz","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jamil, M.A., Singh, S., El-Maarri, O., Oldenburg, J., and Biswas, A. (2022). Exploring Diverse Coagulation Factor XIII Subunit Expression Datasets: A Bioinformatic Analysis. Int J Mol Sci., 23.","DOI":"10.3390\/ijms23094725"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S77","DOI":"10.1016\/j.thromres.2012.02.040","article-title":"Factor XIII and inflammatory cells","volume":"129","author":"Bagoly","year":"2012","journal-title":"Thromb Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Zhang","year":"2002","journal-title":"Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.molmed.2009.06.005","article-title":"p38MAPK: Stress responses from molecular mechanisms to therapeutics","volume":"15","author":"Coulthard","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/sj.cr.7290257","article-title":"Activation and signaling of the p38 MAP kinase pathway","volume":"15","author":"Zarubin","year":"2005","journal-title":"Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1160\/TH07-08-0483","article-title":"Crosstalk between coagulation and inflammation during Dengue virus infection","volume":"99","author":"Izaguirre","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.antiviral.2014.08.004","article-title":"Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580","volume":"110","author":"Fu","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1007\/s00705-019-04406-7","article-title":"Oxidative stress response in the pathogenesis of dengue virus virulence, disease prognosis and therapeutics: An update","volume":"164","author":"Pillai","year":"2019","journal-title":"Arch. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Meuren, L.M., Prestes, E.B., Papa, M.P., de Carvalho, L.R.P., Mustaf\u00e1, Y.M., da Costa, L.S., Da Poian, A.T., Bozza, M.T., and Arruda, L.B. (2022). Infection of endothelial cells by dengue virus induces ROS production by different sources affecting virus replication, cellular activation, death and vascular permeability. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.810376"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"135","DOI":"10.25100\/cm.v46i3.1863","article-title":"A systematic review of observational studies on oxidative\/nitrosative stress involvement in dengue pathogenesis","volume":"46","author":"Castro","year":"2015","journal-title":"Colomb. Medica"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hapugaswatta, H., Wimalasekara, R.L., Perera, S.S., Premaratna, R., Seneviratne, K.N., and Jayathilaka, N. (2021). Expression of Nitric Oxide Synthase and Nitric Oxide Levels in Peripheral Blood Cells and Oxidized Low-Density Lipoprotein Levels in Saliva as Early Markers of Severe Dengue. Biomed. Res. Int., 2021.","DOI":"10.1155\/2021\/6650596"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.3389\/fimmu.2018.03007","article-title":"Neutrophil activation and early features of net formation are associated with dengue virus infection in human","volume":"9","author":"Opasawatchai","year":"2009","journal-title":"Front. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Garishah, F.M., Rother, N., Riswari, S.F., Alisjahbana, B., Overheul, G.J., van Rij, R.P., van der Ven, A., van der Vlag, J., and de Mast, Q. (2021). Neutrophil Extracellular Traps in Dengue Are Mainly Generated NOX-Independently. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.629167"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Liu, K.-T., Liu, Y.-H., Lin, C.-Y., Tsai, M.-J., Hsu, Y.-L., Yen, M.-C., and Kuo, P.-L. (2016). Serum neutrophil gelatinase-associated lipocalin and resistin are associated with dengue infection in adults. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1759-9"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/6\/805\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:44:51Z","timestamp":1760031891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/6\/805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["v17060805"],"URL":"https:\/\/doi.org\/10.3390\/v17060805","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,31]]}}}