{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:49:13Z","timestamp":1789728553871,"version":"4.0.1"},"reference-count":94,"publisher":"American Society for Clinical Investigation","issue":"7","funder":[{"name":"Johns Hopkins University","award":["OD011089"],"award-info":[{"award-number":["OD011089"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH R01HD097608"],"award-info":[{"award-number":["NIH R01HD097608"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100029613","name":"The American Association of Obstetricians and Gynecologists Foundation","doi-asserted-by":"crossref","award":["80028729"],"award-info":[{"award-number":["80028729"]}],"id":[{"id":"10.13039\/100029613","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,4]]},"abstract":"<jats:p>Zika virus (ZIKV) infection during pregnancy causes significant adverse sequelae in the developing fetus, and results in long-term structural and neurologic defects. Most preventive and therapeutic efforts have focused on the development of vaccines, antivirals, and antibodies. The placental immunologic response to ZIKV, however, has been largely overlooked as a target for therapeutic intervention. The placental inflammatory response, specifically IL-1\u03b2 secretion and signaling, is induced by ZIKV infection and represents an environmental factor that is known to increase the risk of perinatal developmental abnormalities. We show in a mouse model that maternally administrated IL-1 receptor antagonist (IRA; Kineret, or anakinra), following ZIKV exposure, can preserve placental function (by improving trophoblast invasion and placental vasculature), increase fetal viability, and reduce neurobehavioral deficits in the offspring. We further demonstrate that while ZIKV RNA is highly detectable in placentas, it is not correlated with fetal viability. Beyond its effects in the placenta, we show that IL-1 blockade may also directly decrease fetal neuroinflammation by mitigating fetal microglial activation in a dose-dependent manner. Our studies distinguish the role of placental inflammation during ZIKV-infected pregnancies, and demonstrate that maternal IRA may attenuate fetal neuroinflammation and improve perinatal outcomes.<\/jats:p>","DOI":"10.1172\/jci.insight.122678","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T13:41:59Z","timestamp":1554298919000},"source":"Crossref","is-referenced-by-count":43,"title":["IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection"],"prefix":"10.1172","volume":"4","author":[{"given":"Jun","family":"Lei","sequence":"first","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan S.","family":"Vermillion","sequence":"additional","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."},{"name":"Department of Molecular and Comparative Pathobiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Jia","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Xie","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xie","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"McLane","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne S.","family":"Sheffield","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3248-1761","authenticated-orcid":true,"given":"Andrew","family":"Pekosz","sequence":"additional","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4576-9636","authenticated-orcid":true,"given":"Amanda","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0730-5224","authenticated-orcid":true,"given":"Sabra L.","family":"Klein","sequence":"additional","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."},{"name":"Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Burd","sequence":"additional","affiliation":[{"name":"Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,2,28]]},"reference":[{"key":"B1","unstructured":"WHO. Situation Report: Zika Virus, Microcephaly, Guillain-Barr\u00e9 Syndrome. https:\/\/www.who.int\/emergencies\/zika-virus\/situation-report\/10-march-2017\/en\/ Posted March 10, 2017. Accessed February 28, 2019"},{"key":"B2","unstructured":"Pan American Health Organization\/WHO. Zika Cases and Congenital Syndrome Associated with Zika Virus Reported by Countries and Territories in the Americas, 2015\u20132017 Cumulative Cases. https:\/\/www.paho.org\/hq\/dmdocuments\/2017\/2017-ago-10-phe-ZIKV-casess.pdf Updated August 10, 2017. Accessed February 25, 2019"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000414"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0000000000000580"},{"issue":"3 pt 2","key":"B5","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/trf.14028","article-title":"Zika virus and blood transfusion: the experience of French Polynesia","volume":"57","author":"Bierlaire","year":"2017","journal-title":"Transfusion"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.01.004"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2017.08.001"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00916-17"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.09.005"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04056-4"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12505"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.05.015"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14575","article-title":"Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes","volume":"8","author":"Vermillion","year":"2017","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01016","article-title":"Zika virus promotes neuronal cell death in a non-cell autonomous manner by triggering the release of neurotoxic factors","volume":"8","author":"Olmo","year":"2017","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix171"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw878"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.01.158"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006004"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16072-3"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1242\/dev.143768"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-015-0445-7"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374921"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903349"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12216"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2014.00108","article-title":"Interleukin-1 receptor blockade in perinatal brain injury","volume":"2","author":"Rosenzweig","year":"2014","journal-title":"Front Pediatr"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.04.003"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004682"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.03.010"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006164"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642627"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006258"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.16-0111"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004658"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.12.010"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.070"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.004"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00125.2015"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02645-3"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nature10897"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2010.01.011"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2014.01.014"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12842"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1177\/1933719117734321"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12798"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathol.2017.08.002"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951115002346"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiph.2016.09.008"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1038\/npjvaccines.2016.21","article-title":"In vivo protection against ZIKV infection and pathogenesis through passive antibody transfer and active immunisation with a prMEnv DNA vaccine","volume":"1","author":"Muthumani","year":"2016","journal-title":"NPJ Vaccines"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12656"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s40506-016-0083-7"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.05.015"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijdevneu.2013.10.003"},{"issue":"109","key":"B53","doi-asserted-by":"crossref","DOI":"10.3791\/53643","article-title":"Induction of maternal immune activation in mice at mid-539 gestation stage with viral mimic poly(I:C)","volume":"2016","author":"Chow","year":"3643","journal-title":"J Vis Exp"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijdevneu.2011.02.011"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082244"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00664.2003"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.07.005"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601600"},{"issue":"2","key":"B59","doi-asserted-by":"crossref","DOI":"10.1095\/biolreprod.115.134627","article-title":"Effects of lipopolysaccharide on human first trimester villous cytotrophoblast cell function in vitro","volume":"94","author":"Li","year":"2016","journal-title":"Biol Reprod"},{"key":"B60","doi-asserted-by":"crossref","DOI":"10.1186\/s12974-015-0330-8","article-title":"Neuronal self-injury mediated by IL-1\u03b2 and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia","volume":"12","author":"Savard","year":"2015","journal-title":"J Neuroinflammation"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/iox081"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(97)00256-6"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(96)00111-7"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2009.01.032"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1159\/000105493"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.05.031"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2015.07.042"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006994"},{"key":"B69","doi-asserted-by":"crossref","DOI":"10.1038\/srep41389","article-title":"Primary Human placental trophoblasts are permissive for Zika virus (ZIKV) replication","volume":"7","author":"Aagaard","year":"2017","journal-title":"Sci Rep"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.07.002"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1002\/path.2257"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1270344"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13980-2"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1600651"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.02.016"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6116"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.01.008"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.10.019"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.58"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/nature18296"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.10.017"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.02.118"},{"issue":"4","key":"B83","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.4049\/jimmunol.161.4.1989","article-title":"IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia","volume":"161","author":"Liu","year":"1998","journal-title":"J Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.etp.2016.11.004"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.06.001"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005168"},{"issue":"12","key":"B87","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1158\/0008-5472.CAN-17-3201","article-title":"Zika virus selectively kills aggressive human embryonal CNS tumor cells in vitro and in vivo","volume":"78","author":"Kaid","year":"2018","journal-title":"Cancer Res"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.008"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao7090"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01691-06"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.041"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-013-1118-0"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3201\/eid1408.080287"},{"key":"B94"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/122678\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:31:22Z","timestamp":1779193882000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/122678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,28]]},"references-count":94,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,2,28]]},"published-print":{"date-parts":[[2019,4,4]]}},"alternative-id":["10.1172\/jci.insight.122678"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.122678","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.735471731.793558929","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,28]]},"article-number":"e122678"}}