{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:28:08Z","timestamp":1790724488000,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI192874"],"award-info":[{"award-number":["R01AI192874"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM125498"],"award-info":[{"award-number":["P20GM125498"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <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 the entry of DENV into Fc\u03b3R-expressing cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, multiple independent groups have shown that B cells are the largest reservoir of virally infected cells in circulation during acute dengue, representing a disconnect in our understanding of immune-mediated DENV tropism. In response to this persistent knowledge gap, our team has previously identified a novel mechanism of immune-mediated enhancement we have termed B cell receptor (BCR)-dependent enhancement (BDE) of DENV infection. In this study, we show that DENV infection of DENV-reactive B cells is highly sensitive to BCR\/DENV envelope (E) protein interactions. DENV entry into this subset of B cells is dynamin-mediated, requires proximal BCR signaling, and involves localization to late endosomes. Finally, we show that immortalized DENV-reactive B cells are productively infected by live DENV, capable of supporting active viral replication of all four serotypes. We propose that BDE provides an additional layer of pathogen-specific immune-mediated infection risk that complements existing models of ADE and offers additional insight into potential mechanisms of DENV immunopathogenesis.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>This study provides mechanistic insight into the process of B cell receptor (BCR)-dependent enhancement of dengue virus (DENV) infection. Immune-mediated enhancement of infection is a cornerstone of dengue immunopathogenesis and is most often attributed to antibody-dependent enhancement (ADE). BCR-dependent enhancement of DENV infection is an alternative and complementary mechanism for immune-mediated enhancement that addresses several persistent knowledge gaps in the dengue field and may offer mechanistic insight into why some people progress to severe dengue after infection.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.02216-25","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:00:46Z","timestamp":1784552446000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Molecular and biophysical requirements for B cell receptor-dependent enhancement of dengue virus infection"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5911-0429","authenticated-orcid":false,"given":"Gaby","family":"Madrigal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Cellular and Molecular Biomedical Sciences Graduate Program, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2043-4490","authenticated-orcid":false,"given":"Chad","family":"Gebo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/040kfrw16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, State University of New York Upstate Medical University","place":["Syracuse, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"McElvany","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine","place":["Burlington, USA"]},{"name":"Vaccine Testing Center, University of Vermont Larner College of Medicine","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menelaos","family":"Symeonides","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Cellular and Molecular Biomedical Sciences Graduate Program, University of Vermont","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Translational Global Infectious Diseases Research Center, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9700-235X","authenticated-orcid":true,"given":"Sean A.","family":"Diehl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Cellular and Molecular Biomedical Sciences Graduate Program, University of Vermont","place":["Burlington, USA"]},{"name":"Vaccine Testing Center, University of Vermont Larner College of Medicine","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Translational Global Infectious Diseases Research Center, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-6714","authenticated-orcid":true,"given":"Adam T.","family":"Waickman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/040kfrw16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, State University of New York Upstate Medical University","place":["Syracuse, USA"]},{"id":[{"id":"https:\/\/ror.org\/040kfrw16","id-type":"ROR","asserted-by":"publisher"}],"name":"Global Health Institute, State University of New York Upstate Medical University","place":["Syracuse, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12060"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2011.10-0503"},{"key":"e_1_3_4_4_2","unstructured":"Organization WH. 2023. Dengue and severe dengue. Available from: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue"},{"key":"e_1_3_4_5_2","first-page":"272","article-title":"Risk factors of dengue shock syndrome in children","volume":"90","author":"Tantracheewathorn T","year":"2007","unstructured":"Tantracheewathorn T, Tantracheewathorn S. 2007. Risk factors of dengue shock syndrome in children. J Med Assoc Thai 90:272\u2013277.","journal-title":"J Med Assoc Thai"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1997.56.566"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0157-4"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0065-3527(03)60011-4"},{"key":"e_1_3_4_9_2","first-page":"24","article-title":"Immunological enhancement of dengue virus replication","volume":"243","author":"Halstead SB","year":"1973","unstructured":"Halstead SB, Chow JS, Marchette NJ. 1973. Immunological enhancement of dengue virus replication. Nat New Biol 243:24\u201326.","journal-title":"Nat New Biol"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6836"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.146.1.201"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.AID-0022-2014"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.146.1.218"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00410-0"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aai8128"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2022.e11212"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.21051"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-018-0482-9"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01568-07"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65939-5"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594813"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1813819115"},{"key":"e_1_3_4_23_2","first-page":"1352","article-title":"Flow cytometric analysis of dengue virus-infected cells in peripheral blood","volume":"41","author":"Baclig MO","year":"2010","unstructured":"Baclig MO, Gervacio LTS, Suarez L-AC, Buerano CC, Matias RR, Kumatori A, Inoue S, Morita K, Natividad FF, Hasebe F. 2010. Flow cytometric analysis of dengue virus-infected cells in peripheral blood. Southeast Asian J Trop Med Public Health 41:1352\u20131358.","journal-title":"Southeast Asian J Trop Med Public Health"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143391"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09434-0"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012683"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.03.002"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102079"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00681-24"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2005.10.030"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.11.042"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00116-07"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006685"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140824"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000244"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001131"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2018.08.013"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01654-3"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005554"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2018.09.019"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0156-5"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.07.029"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2071"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2001.65.405"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.43.7.3267-3272.2005"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.2006.01706.x"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.02216-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.02216-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:03:08Z","timestamp":1787058188000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/jvi.02216-25"}},"subtitle":[],"editor":[{"given":"Guangxiang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":47,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,18]]}},"alternative-id":["10.1128\/jvi.02216-25"],"URL":"https:\/\/doi.org\/10.1128\/jvi.02216-25","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"assertion":[{"value":"2025-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02216-25"}}