{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:13:32Z","timestamp":1792145612924,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100007258","name":"State University of New York","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007258","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Defense, Medical Research and Material Command."},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI141997-06 and P20GM125498"],"award-info":[{"award-number":["U01AI141997-06 and P20GM125498"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into Fc\u03b3R expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectible B cells increases in previously flavivirus-na\u00efve volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012683","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T13:48:49Z","timestamp":1730382529000},"page":"e1012683","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["B cell receptor dependent enhancement of dengue virus infection"],"prefix":"10.1371","volume":"20","author":[{"given":"Chad","family":"Gebo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line S. C.","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"McElvany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy R.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph Q.","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shima","family":"Moradpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Currier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Friberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Gromowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary C.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean A.","family":"Diehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-6714","authenticated-orcid":true,"given":"Adam T.","family":"Waickman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ppat.1012683.ref001","article-title":"Dengue and severe dengue World Health Organization","author":"Organization WH"},{"issue":"2","key":"ppat.1012683.ref002","first-page":"272","article-title":"Risk factors of dengue shock syndrome in children","volume":"90","author":"T Tantracheewathorn","year":"2007","journal-title":"J Med Assoc Thai"},{"issue":"5","key":"ppat.1012683.ref003","doi-asserted-by":"crossref","first-page":"566","DOI":"10.4269\/ajtmh.1997.56.566","article-title":"Risk factors in dengue shock syndrome","volume":"56","author":"S Thein","year":"1997","journal-title":"Am J Trop Med Hyg"},{"issue":"7446","key":"ppat.1012683.ref004","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"},{"issue":"7707","key":"ppat.1012683.ref005","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41586-018-0157-4","article-title":"Reconstruction of antibody dynamics and infection histories to evaluate dengue risk","volume":"557","author":"H Salje","year":"2018","journal-title":"Nature"},{"issue":"1","key":"ppat.1012683.ref006","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1084\/jem.146.1.201","article-title":"Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody","volume":"146","author":"SB Halstead","year":"1977","journal-title":"J Exp Med"},{"issue":"1","key":"ppat.1012683.ref007","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1084\/jem.146.1.218","article-title":"Dengue viruses and mononuclear phagocytes. II. Identity of blood and tissue leukocytes supporting in vitro infection","volume":"146","author":"SB Halstead","year":"1977","journal-title":"J Exp Med"},{"issue":"10","key":"ppat.1012683.ref008","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41577-020-00410-0","article-title":"The role of IgG Fc receptors in antibody-dependent enhancement","volume":"20","author":"S Bournazos","year":"2020","journal-title":"Nat Rev Immunol"},{"issue":"6323","key":"ppat.1012683.ref009","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1126\/science.aai8128","article-title":"IgG antibodies to dengue enhanced for FcgammaRIIIA binding determine disease severity","volume":"355","author":"TT Wang","year":"2017","journal-title":"Science"},{"key":"ppat.1012683.ref010","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0065-3527(03)60011-4","article-title":"Neutralization and antibody-dependent enhancement of dengue viruses","volume":"60","author":"SB Halstead","year":"2003","journal-title":"Adv Virus Res"},{"issue":"1","key":"ppat.1012683.ref011","doi-asserted-by":"crossref","first-page":"154","DOI":"10.4269\/ajtmh.1983.32.154","article-title":"Original antigenic sin in dengue","volume":"32","author":"SB Halstead","year":"1983","journal-title":"Am J Trop Med Hyg"},{"issue":"2","key":"ppat.1012683.ref012","doi-asserted-by":"crossref","first-page":"411","DOI":"10.4269\/ajtmh.1988.38.411","article-title":"Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants","volume":"38","author":"SC Kliks","year":"1988","journal-title":"Am J Trop Med Hyg"},{"issue":"12","key":"ppat.1012683.ref013","doi-asserted-by":"crossref","first-page":"e51335","DOI":"10.1371\/journal.pone.0051335","article-title":"Dengue viral RNA levels in peripheral blood mononuclear cells are associated with disease severity and preexisting dengue immune status","volume":"7","author":"A Srikiatkhachorn","year":"2012","journal-title":"PLoS One"},{"issue":"52","key":"ppat.1012683.ref014","doi-asserted-by":"crossref","first-page":"E12363","DOI":"10.1073\/pnas.1813819115","article-title":"Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue","volume":"115","author":"F Zanini","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1012683.ref015","first-page":"9047","article-title":"Analysis of cell-associated DENV RNA by oligo(dT) primed 5\u2019 capture scRNAseq","volume":"10","author":"MA Sanborn","year":"2020"},{"issue":"12","key":"ppat.1012683.ref016","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1038\/s41590-023-01654-3","article-title":"Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach","volume":"24","author":"L Ghita","year":"2023","journal-title":"Nat Immunol"},{"key":"ppat.1012683.ref017","doi-asserted-by":"crossref","first-page":"594813","DOI":"10.3389\/fimmu.2020.594813","article-title":"Direct Infection of B Cells by Dengue Virus Modulates B Cell Responses in a Cambodian Pediatric Cohort","volume":"11","author":"V Upasani","year":"2020","journal-title":"Front Immunol"},{"issue":"4","key":"ppat.1012683.ref018","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.imbio.2015.12.003","article-title":"Human B cells have an active phagocytic capability and undergo immune activation upon phagocytosis of Mycobacterium tuberculosis","volume":"221","author":"Q Zhu","year":"2016","journal-title":"Immunobiology"},{"issue":"9","key":"ppat.1012683.ref019","doi-asserted-by":"crossref","DOI":"10.15252\/embr.201846016","article-title":"Antigen phagocytosis by B cells is required for a potent humoral response","volume":"19","author":"A Martinez-Riano","year":"2018","journal-title":"EMBO Rep"},{"issue":"1","key":"ppat.1012683.ref020","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.virol.2005.10.030","article-title":"A rapid and quantitative assay for measuring antibody-mediated neutralization of West Nile virus infection","volume":"346","author":"TC Pierson","year":"2006","journal-title":"Virology"},{"issue":"1","key":"ppat.1012683.ref021","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.virol.2008.08.021","article-title":"Temperature-dependent production of pseudoinfectious dengue reporter virus particles by complementation","volume":"381","author":"C Ansarah-Sobrinho","year":"2008","journal-title":"Virology"},{"issue":"1","key":"ppat.1012683.ref022","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nm.2071","article-title":"Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming","volume":"16","author":"MJ Kwakkenbos","year":"2010","journal-title":"Nat Med"},{"issue":"1\u20132","key":"ppat.1012683.ref023","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jviromet.2005.12.002","article-title":"An immunocytometric assay based on dengue infection via DC-SIGN permits rapid measurement of anti-dengue neutralizing antibodies","volume":"134","author":"NC Martin","year":"2006","journal-title":"J Virol Methods"},{"issue":"9","key":"ppat.1012683.ref024","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.4049\/jimmunol.147.9.3139","article-title":"Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fc gamma receptors","volume":"147","author":"BJ Mady","year":"1991","journal-title":"J Immunol"},{"issue":"8","key":"ppat.1012683.ref025","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1038\/s41591-021-01392-9","article-title":"Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection","volume":"27","author":"H Salje","year":"2021","journal-title":"Nat Med"},{"issue":"6365","key":"ppat.1012683.ref026","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1126\/science.aan6836","article-title":"Antibody-dependent enhancement of severe dengue disease in humans","volume":"358","author":"LC Katzelnick","year":"2017","journal-title":"Science"},{"issue":"10","key":"ppat.1012683.ref027","doi-asserted-by":"crossref","first-page":"4969","DOI":"10.4049\/jimmunol.171.10.4969","article-title":"Cutting edge: long-term B cell memory in humans after smallpox vaccination","volume":"171","author":"S Crotty","year":"2003","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1012683.ref028","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1038\/s41564-024-01668-z","article-title":"Low-dose dengue virus 3 human challenge model: a phase 1 open-label study.","volume":"9","author":"AT Waickman","year":"2024","journal-title":"Nat Microbiol"},{"issue":"7","key":"ppat.1012683.ref029","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1128\/JCM.43.7.3267-3272.2005","article-title":"Flow cytometry-based assay for titrating dengue virus","volume":"43","author":"CR Lambeth","year":"2005","journal-title":"J Clin Microbiol"},{"key":"ppat.1012683.ref030","doi-asserted-by":"crossref","first-page":"777672","DOI":"10.3389\/fimmu.2021.777672","article-title":"Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection.","volume":"12","author":"AD Wegman","year":"2021","journal-title":"Front Immunol"},{"key":"ppat.1012683.ref031","doi-asserted-by":"crossref","first-page":"102733","DOI":"10.1016\/j.ebiom.2020.102733","article-title":"Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection","volume":"54","author":"AT Waickman","year":"2020","journal-title":"EBioMedicine"},{"key":"ppat.1012683.ref032","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.ebiom.2019.02.060","article-title":"Longitudinal analysis of acute and convalescent B cell responses in a human primary dengue serotype 2 infection model.","volume":"41","author":"UK Nivarthi","year":"2019","journal-title":"EBioMedicine."},{"issue":"330","key":"ppat.1012683.ref033","article-title":"The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.","volume":"8","author":"BD Kirkpatrick","year":"2016"},{"issue":"8","key":"ppat.1012683.ref034","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.124588","article-title":"Human antibody response to Zika targets type-specific quaternary structure epitopes","volume":"4","author":"MH Collins","year":"2019","journal-title":"JCI Insight"},{"issue":"18","key":"ppat.1012683.ref035","doi-asserted-by":"crossref","first-page":"9854","DOI":"10.1128\/JVI.01278-12","article-title":"A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny","volume":"86","author":"CM O\u2019Connor","year":"2012","journal-title":"J Virol"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1012683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T13:41:10Z","timestamp":1731418870000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012683"}},"subtitle":[],"editor":[{"given":"Thomas E.","family":"Morrison","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1012683","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.06.27.601099","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}