{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T17:39:07Z","timestamp":1774805947199,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FDA Perinatal Health Center of Excellence and CBER\/FDA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>As a developmental toxicant, Zika virus (ZIKV) attacks both the growing nervous system, causing congenital Zika syndrome, and the placenta, resulting in pathological changes and associated adverse fetal outcomes. There are no vaccines, antibodies, or other treatments for ZIKV, despite the potential for its re-emergence. Multiple studies have highlighted the risk of antibodies for enhancing ZIKV infection, including during pregnancy, but the mechanisms for such effects are not fully understood. We have focused on the ability of the neonatal Fc receptor (FcRn) to interact with ZIKV in the presence and absence of relevant antibodies. We found that ZIKV replication was higher in Marvin Darby Canine Kidney (MDCK) cells that overexpress FcRn compared to those that do not, and knocking down FcRn decreased ZIKV RNA production. In the placenta trophoblast BeWo cell line, ZIKV infection itself downregulated FcRn at the mRNA and protein levels. Addition of anti-ZIKV antibodies to MDCK\/FcRn cells resulted in non-monotonous neutralization curves with neutralization attenuation and even enhancement of infection at higher concentrations. Non-monotonous neutralization was also seen in BeWo cells at intermediate antibody concentrations. Our studies highlight the underappreciated role FcRn plays in ZIKV infection and may have implications for anti-ZIKV prophylaxis and therapy in pregnant women.<\/jats:p>","DOI":"10.3390\/vaccines10122059","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T01:54:31Z","timestamp":1669859671000},"page":"2059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Zika Virus Infection and Antibody Neutralization in FcRn Expressing Placenta and Engineered Cell Lines"],"prefix":"10.3390","volume":"10","author":[{"given":"Yanqun","family":"Xu","sequence":"first","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"He","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanaz","family":"Momben-Abolfath","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin","family":"Vertrees","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malgorzata G.","family":"Norton","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-4174","authenticated-orcid":false,"given":"Evi Budo","family":"Struble","sequence":"additional","affiliation":[{"name":"Laboratory of Plasma Derivatives, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","article-title":"Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure","volume":"165","author":"Qian","year":"2016","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e12744","DOI":"10.1111\/cmi.12744","article-title":"Zika infection and the development of neurological defects","volume":"19","author":"Russo","year":"2017","journal-title":"Cell Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jamapediatrics.2016.3982","article-title":"Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians","volume":"171","author":"Moore","year":"2017","journal-title":"JAMA Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-0716-0581-3_18","article-title":"Zika Virus Targets Multiple Tissues and Cell Types During the First Trimester of Pregnancy","volume":"2142","author":"Veas","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s42003-022-03158-6","article-title":"ZIKV can infect human term placentas in the absence of maternal factors","volume":"5","author":"Wuertz","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.3389\/fimmu.2020.02146","article-title":"Zika Induces Human Placental Damage and Inflammation","volume":"11","author":"Rabelo","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41467-017-02499-9","article-title":"Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology","volume":"9","author":"Hirsch","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1097\/AOG.0000000000003577","article-title":"Maternal Zika Virus Infection: Association With Small-for-Gestational-Age Neonates and Preterm Birth","volume":"134","author":"Cooper","year":"2019","journal-title":"Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e0008893","DOI":"10.1371\/journal.pntd.0008893","article-title":"Adverse fetal and neonatal outcomes in pregnancies with confirmed Zika Virus infection in Rio de Janeiro, Brazil: A cohort study","volume":"15","author":"Souza","year":"2021","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.chom.2018.10.008","article-title":"Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages","volume":"24","author":"Zimmerman","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eaav3208","DOI":"10.1126\/sciadv.aav3208","article-title":"Maternal immunity and antibodies to dengue virus promote infection and Zika virus-induced microcephaly in fetuses","volume":"5","author":"Rathore","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xu, Y., He, Y., Momben-Abolfath, S., Eller, N., Norton, M., Zhang, P., Scott, D., and Struble, E.B. (2021). Entry and Disposition of Zika Virus Immune Complexes in a Tissue Culture Model of the Maternal-Fetal Interface. Vaccines, 9.","DOI":"10.3390\/vaccines9020145"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/s41467-018-03061-x","article-title":"A human endothelial cell-based recycling assay for screening of FcRn targeted molecules","volume":"9","author":"Grevys","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/imr.12331","article-title":"The multiple facets of FcRn in immunity","volume":"268","author":"Stapleton","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.3389\/fimmu.2019.01540","article-title":"The Neonatal Fc Receptor (FcRn): A Misnomer?","volume":"10","author":"Pyzik","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.placenta.2019.02.012","article-title":"Expression of the neonatal Fc-receptor in placental-fetal endothelium and in cells of the placental immune system","volume":"78","author":"Kiskova","year":"2019","journal-title":"Placenta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.cell.2019.05.044","article-title":"Fc Glycan-Mediated Regulation of Placental Antibody Transfer","volume":"178","author":"Jennewein","year":"2019","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1080\/19420862.2019.1605270","article-title":"An in vitro FcRn- dependent transcytosis assay as a screening tool for predictive assessment of nonspecific clearance of antibody therapeutics in humans","volume":"11","author":"Chung","year":"2019","journal-title":"MAbs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.immuni.2004.05.007","article-title":"Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells","volume":"20","author":"Yoshida","year":"2004","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1038\/s41467-019-10865-y","article-title":"Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor","volume":"10","author":"Liu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.cell.2019.04.035","article-title":"Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B","volume":"177","author":"Zhao","year":"2019","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e0116622","DOI":"10.1128\/mbio.01166-22","article-title":"Human FcRn Is a Two-in-One Attachment-Uncoating Receptor for Echovirus 18","volume":"13","author":"Chen","year":"2022","journal-title":"mBio"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/infdis\/jiaa383","article-title":"Zika Virus Changes Methylation of Genes Involved in Immune Response and Neural Development in Brazilian Babies Born With Congenital Microcephaly","volume":"223","author":"Anderson","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Polonio, C.M., and Peron, J.P.S. (2021). ZIKV Infection and miRNA Network in Pathogenesis and Immune Response. Viruses, 13.","DOI":"10.3390\/v13101992"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1126\/science.aaf8505","article-title":"Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection","volume":"353","author":"Stettler","year":"2016","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e02015-19","DOI":"10.1128\/JVI.02015-19","article-title":"Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry","volume":"94","author":"Wan","year":"2020","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/19420862.2015.1008353","article-title":"The neonatal Fc receptor (FcRn) binds independently to both sites of the IgG homodimer with identical affinity","volume":"7","author":"Abdiche","year":"2015","journal-title":"MAbs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1016\/j.cell.2021.06.021","article-title":"In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies","volume":"184","author":"Li","year":"2021","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1021\/acsinfecdis.6b00006","article-title":"Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates","volume":"2","author":"Wang","year":"2016","journal-title":"ACS Infect. Dis."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/12\/2059\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:30:53Z","timestamp":1760146253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/12\/2059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["vaccines10122059"],"URL":"https:\/\/doi.org\/10.3390\/vaccines10122059","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]}}}