Interleukin-27 is antiviral at the maternal-fetal interface.

Interleukin-27 is antiviral at the maternal-fetal interface. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Interleukin-27 is antiviral at the maternal-fetal interface. Kellie Ann Jurado, Madeline Merlino, Briah Barksdale, Seble Negatu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6513464/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Dec, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and a diverse repertoire of cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface. Interleukin 27 (IL-27) is a highly expressed cytokine in the placenta whose functional consequence during congenital infection is unknown. Here, we utilized trophoblast organoids (TO) derived from primary human placentas and a mouse model of congenital viral infection to uncover the functional role of IL-27 signaling during pregnancy. We show that TOs constitutively express IL-27 and its receptor, IL27RA, and demonstrate that IL-27 signaling restricts Zika virus (ZIKV) infection of TOs. Through bulk RNA-sequencing of TOs in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical within the context of congenital murine ZIKV infection, as IL-27 restricts placental ZIKV burdens and protects against pathologic fetal outcomes early in gestation. These findings collectively demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection. Biological sciences/Immunology/Infectious diseases/Viral infection Biological sciences/Microbiology/Virology/Viral host response Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.pdf Supplemental Figures SupplementaryTables.xlsx Supplemental Tables Cite Share Download PDF Status: Published Journal Publication published 19 Dec, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6513464","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":453388033,"identity":"4e0d0a67-ab57-4a4b-978b-a46ae4fb1c57","order_by":0,"name":"Kellie Ann Jurado","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-0466-2696","institution":"University of Pennsylvania","correspondingAuthor":true,"prefix":"","firstName":"Kellie","middleName":"Ann","lastName":"Jurado","suffix":""},{"id":453388034,"identity":"ac20cf2b-2d0c-4606-8505-a7fa06b3459e","order_by":1,"name":"Madeline Merlino","email":"","orcid":"","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Madeline","middleName":"","lastName":"Merlino","suffix":""},{"id":453388035,"identity":"22eca2e9-6897-4dd0-b0ec-cc1592ba5827","order_by":2,"name":"Briah Barksdale","email":"","orcid":"","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Briah","middleName":"","lastName":"Barksdale","suffix":""},{"id":453388036,"identity":"13b8e9b5-8d39-4794-897e-9cf509207003","order_by":3,"name":"Seble Negatu","email":"","orcid":"","institution":"university of pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Seble","middleName":"","lastName":"Negatu","suffix":""},{"id":453388037,"identity":"34e103d5-84b8-47e1-b9d1-3f2af019d250","order_by":4,"name":"Rebecca Clements","email":"","orcid":"https://orcid.org/0000-0001-9726-1554","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Clements","suffix":""},{"id":453388038,"identity":"bb0e152b-9853-4bab-91f6-311d054f5052","order_by":5,"name":"Taylor Miller-Ensminger","email":"","orcid":"","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Taylor","middleName":"","lastName":"Miller-Ensminger","suffix":""},{"id":453388039,"identity":"5f4b5eb2-9ddf-4d93-a542-1db4f30d162f","order_by":6,"name":"Alexandra Lopez","email":"","orcid":"","institution":"UT Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Lopez","suffix":""},{"id":453388040,"identity":"3d5d10e9-d00c-4160-954c-2ab84784e8cc","order_by":7,"name":"Sneha Mani","email":"","orcid":"","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Sneha","middleName":"","lastName":"Mani","suffix":""},{"id":453388041,"identity":"c0a2ac6f-da8c-4b21-bc09-0684b9e68f13","order_by":8,"name":"Monica Mainigi","email":"","orcid":"","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"","lastName":"Mainigi","suffix":""},{"id":453388042,"identity":"7dd5329f-efa7-47ec-9d30-27319e2a905e","order_by":9,"name":"Christopher Hunter","email":"","orcid":"https://orcid.org/0000-0003-3092-1428","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Hunter","suffix":""}],"badges":[],"createdAt":"2025-04-23 14:10:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6513464/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6513464/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-67378-0","type":"published","date":"2025-12-19T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":100662078,"identity":"89fcff36-8fa8-4a97-b015-1c69fa845ffa","added_by":"auto","created_at":"2026-01-20 08:54:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1345066,"visible":true,"origin":"","legend":"Article File","description":"","filename":"IL27ManuscriptandFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6513464/v1_covered_633c89f0-57ed-4bdb-a021-1cf8772f4000.pdf"},{"id":83959888,"identity":"f58e6e3a-988c-4378-a270-312320580d18","added_by":"auto","created_at":"2025-06-05 04:44:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":513229,"visible":true,"origin":"","legend":"Supplemental Figures","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6513464/v1/475f1384f31f3dca8f9f8a73.pdf"},{"id":83959885,"identity":"4e9fe4e9-d1b0-4126-8c01-6b8677047b18","added_by":"auto","created_at":"2025-06-05 04:44:43","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":48348,"visible":true,"origin":"","legend":"Supplemental Tables","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6513464/v1/41a249aa823e5cebe3baa805.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Interleukin-27 is antiviral at the maternal-fetal interface.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6513464/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6513464/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and a diverse repertoire of cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface. Interleukin 27 (IL-27) is a highly expressed cytokine in the placenta whose functional consequence during congenital infection is unknown. Here, we utilized trophoblast organoids (TO) derived from primary human placentas and a mouse model of congenital viral infection to uncover the functional role of IL-27 signaling during pregnancy. We show that TOs constitutively express IL-27 and its receptor, IL27RA, and demonstrate that IL-27 signaling restricts Zika virus (ZIKV) infection of TOs. Through bulk RNA-sequencing of TOs in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical within the context of congenital murine ZIKV infection, as IL-27 restricts placental ZIKV burdens and protects against pathologic fetal outcomes early in gestation. These findings collectively demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection.","manuscriptTitle":"Interleukin-27 is antiviral at the maternal-fetal interface.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-05 04:44:39","doi":"10.21203/rs.3.rs-6513464/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7bfe9ea8-1817-4715-8a63-cb3e3b7b1007","owner":[],"postedDate":"June 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":48216514,"name":"Biological sciences/Immunology/Infectious diseases/Viral infection"},{"id":48216515,"name":"Biological sciences/Microbiology/Virology/Viral host response"}],"tags":[],"updatedAt":"2026-01-20T08:30:39+00:00","versionOfRecord":{"articleIdentity":"rs-6513464","link":"https://doi.org/10.1038/s41467-025-67378-0","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-12-19 05:00:00","publishedOnDateReadable":"December 19th, 2025"},"versionCreatedAt":"2025-06-05 04:44:39","video":"","vorDoi":"10.1038/s41467-025-67378-0","vorDoiUrl":"https://doi.org/10.1038/s41467-025-67378-0","workflowStages":[]},"version":"v1","identity":"rs-6513464","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6513464","identity":"rs-6513464","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}