A human cerebral organoid model of West Nile virus encephalitis shows innate immunocompetency

A human cerebral organoid model of West Nile virus encephalitis shows innate immunocompetency | 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 A human cerebral organoid model of West Nile virus encephalitis shows innate immunocompetency Johanna Steffen, Lina Widerspick, Stephanie Jansen, Dennis Tappe This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6975922/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract West Nile virus (WNV), an arbovirus of emerging global interest, can cause neuroinvasive disease in humans. Currently, no protective vaccine or specific treatment is available for human WNV encephalitis. The virus induces neuronal cell death, while astrocytes and microglia, cells important in the antiviral defense of the central nervous system, are suspected to contribute to WNV pathology. Hence, understanding their role is crucial for future treatment approaches. However, human data is limited, and animal models as well as in vitro monocultures have inherent limitations. In this study, human cerebral organoids forming complex 3D in vitro structures including neurons, astrocytes and microglia were used as a novel WNV encephalitis model. Exposure of 100-day-old cerebral organoids to WNV resulted in robust infection leading to heterogenous courses. An early strong viral replication was shown to potentially result in viral clearance, while a late peak resulted in more long-term infection. Viral foci were seen in cortical-like areas, rich in neurons and astrocytes, however void of microglia. Pro-inflammatory cytokines (IL-6, TNF-α, IL-18), chemokines (CXCL10, CCL17, CX3CL1, CCL2) and biomarkers (IL-1RA, sTREM-1, sRAGE, BDNF) were increasingly released. Conclusively, human cerebral organoids make suitable novel WNV encephalitis models with outstanding properties to study acute and long-term infection. Biological sciences/Immunology/Innate immunity Biological sciences/Microbiology/Virology/West nile virus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFigure1cytokineschemokines.pdf Supplementary Figure 1 SupplementaryFigure2otherbiomarkers.pdf Supplementary Figure 2 SupplementaryFigure3longtermcytokineschemokines.pdf Supplementary Figure 3 SupplementaryFigure4longtermotherbiomarkers.pdf Supplementary Figure 4 SupplementaryFigure5groupscytokines.pdf Supplementary Figure 5 SupplementaryFigure6groupschemokines.pdf Supplementary Figure 6 SupplementaryFigure7groupsbiomarkers1.pdf Supplementary Figure 7 SupplementaryFigure8groupsbiomarkers2.pdf Supplementary Figure 8 Cite Share Download PDF Status: Published Journal Publication published 07 Mar, 2026 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. 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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-6975922","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":488715074,"identity":"e911f09c-a8a5-4ea1-98aa-d98016020c4e","order_by":0,"name":"Johanna Steffen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIie2Pv0vDQBTHvyGQ6YKrEMj9CxcC7RDwb2koeEs6uAUUeiFwWeoeUfBf6KbdchzEJTgXdPAHOFs6CmIUq1C44uhwn+m9B5/3fQ+wWP4hjiC/zWsOhKyf9bX7B8WDU3dA3CuF2KUAW0o6x1eMWXGrU7U+uj4AvSyVaPJ7fhWU1dMSSWg8bHY7Ds66MVjrpaLpXiaLC1WUGXhsVOqMBb50wTwyfF5JPZkv009Fp8KsxG++nILKvZVQ75qzb2W6Qxn0KRpoiSOU0KONMjL/0g0SX94Q1h5Goml1tKjT4jxjPDKlRNUsvvPlcUhL/SiaE02H+/xhneUJNaVsdpGtOTMJgHGXxWKxWH74AIzjXnCmmAULAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0007-8860-8537","institution":"Bernhard Nocht Institute for Tropical Medicine","correspondingAuthor":true,"prefix":"","firstName":"Johanna","middleName":"","lastName":"Steffen","suffix":""},{"id":488715075,"identity":"f8606625-ac94-4cf8-bde1-c48ce058b445","order_by":1,"name":"Lina Widerspick","email":"","orcid":"https://orcid.org/0000-0001-6666-7770","institution":"Bernhard-Nocht-Institute for Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Widerspick","suffix":""},{"id":488715076,"identity":"e2d860f4-c9e2-4d90-841a-00277f793a38","order_by":2,"name":"Stephanie Jansen","email":"","orcid":"https://orcid.org/0000-0002-4623-5070","institution":"Bernhard Nocht Institute for Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Jansen","suffix":""},{"id":488715077,"identity":"db1a84b6-7a38-4e40-bc50-09f15fdaf98d","order_by":3,"name":"Dennis Tappe","email":"","orcid":"","institution":"Bernhard Nocht-Institute for Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dennis","middleName":"","lastName":"Tappe","suffix":""}],"badges":[],"createdAt":"2025-06-25 14:50:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6975922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6975922/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-026-70281-x","type":"published","date":"2026-03-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87371073,"identity":"a855334a-8fd4-4069-bcf5-de73ccb6403b","added_by":"auto","created_at":"2025-07-23 07:09:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79457,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrouping of human WNV-infected human cerebral organoids.\u003c/strong\u003e As the infection of human cerebral organoids with WNV resulted in heterogenous growth \u0026nbsp;kinetics, subgrouping was performed based on two factors. First, their morphology, hence the \u0026nbsp;presence (ChP) or absence (CerOrg) of choroid plexus structures. Second, the observed course \u0026nbsp;of infection, differentiating between organoids that reached their highest viral titer until 4 dpi \u0026nbsp;(Type A) or later until 14 dpi (Type B). Partially created using BioRender.com.\u003c/p\u003e","description":"","filename":"Figure1groups.png","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/127902728ad45dd8fbe73c42.png"},{"id":87371067,"identity":"88b927f2-4571-4650-baa2-ec06604aded8","added_by":"auto","created_at":"2025-07-23 07:09:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24974,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWNV replication in infected human cerebral organoids. \u003c/strong\u003eHuman cerebral organoids were infected with 1 x 104 WNV infectious particles. Results were \u0026nbsp;obtained in two independent experiments, both sampling to at least 14 dpi, whereby one \u0026nbsp;experiment additionally included 21 and 28 dpi. Organoids were morphologically \u0026nbsp;distinguished upon the (a) absence or (b) presence of choroid plexus (ChP) structures. In \u0026nbsp;retrospect, organoids were furthermore grouped by the course of infection observed. Type A \u0026nbsp;included organoids reaching their highest viral load until 4dpi, whereas Type B organoids \u0026nbsp;reached their highest viral load later than 4 dpi. The solid line in the graphs to the left is drawn \u0026nbsp;through median values. The solid lines in the graphs to the right are drawn through the values \u0026nbsp;of the individual organoids. The overall sample size of minimum n=24 at 14 dpi and n=12 at \u0026nbsp;28 dpi, was reduced to minimum n=5 at 14 dpi and minimum n=2 at 28 dpi upon previously \u0026nbsp;described subgrouping. Limit of detection (LOD): 88.5 x 10 2 FFU/ml.\u003c/p\u003e","description":"","filename":"Figure2replication.png","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/5cf05b149b65a69c56539cbd.png"},{"id":87371070,"identity":"ab651680-168a-43ca-8857-197edfa1e81b","added_by":"auto","created_at":"2025-07-23 07:09:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3855880,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWNV infection localizes to outer cortical-like areas of human cerebral organoids.\u003c/strong\u003e Immunofluorescence staining of WNV-infected human cerebral organoids were stained for \u0026nbsp;WNV envelope protein, adult neurons (MAP2), astrocytes (GFAP) or microglia (CD68) and cell \u0026nbsp;nuclei (DAPI). Depicted is one infected organoid at 14 dpi. (a) The staining revealed WNV \u0026nbsp;envelope protein in small foci in outer areas of the organoids. These areas were observed to \u0026nbsp;be rich in adult neurons and astrocytes. (b) No microglia were detected in the areas positive \u0026nbsp;for WNV envelope protein. Instead, singular microglia were observed throughout the \u0026nbsp;organoids. Scale bars, 100 µm.\u003c/p\u003e","description":"","filename":"Figure3immunofluorescencestaining.png","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/6792d99325aceb99c29fe7bf.png"},{"id":87371054,"identity":"a7fc4b1e-7f35-4cdd-8ade-cea148478832","added_by":"auto","created_at":"2025-07-23 07:09:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40493,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTemporal release of diverse biomarkers by WNV-infected human cerebral \u0026nbsp;organoids.\u003c/strong\u003e Screening of supernatants of WNV-infected human cerebral organoids for cytokines, \u0026nbsp;chemokines and other biomarkers in the acute phase until 14 dpi (2 independent experiments) \u0026nbsp;and the post-acute phase until 28 dpi (1 experiment) using a bead-based LegendPlexTM assay. \u0026nbsp;Acute and post-acute phase were analyzed individually using a mixed-effects model (REML) \u0026nbsp;with Šídák’s multiple comparing the differences between infected organoids and uninfected \u0026nbsp;controls. A statistically significant increase is marked by a solid line (p \u0026lt; 0.05). Non-significant \u0026nbsp;results between significant comparisons are marked by a dashed line (p \u0026gt; 0.05). C-C motif \u0026nbsp;chemokine 17 (CCL17). C-C motif chemokine 2 (CCL2). C-X3-C motif chemokine 1 (CX3CL1). C-X-C motif chemokine 10 (CXCL10). Brain-derived neurotropic factor (BDNF). Interleukin 1 \u0026nbsp;receptor antagonist protein (IL-1RA). Interleukin 6 (IL-6). Interleukin 18 (IL-18). Soluble \u0026nbsp;receptor for advanced glycosylation end products (sRAGE). Soluble triggering receptor \u0026nbsp;expressed on myeloid cells 1 (sTREM-1). Tumor necrosis factor alpha (TNF-α).\u003c/p\u003e","description":"","filename":"Figure4markerreleasetimeline.png","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/9e5b9322de6a8408d88d1801.png"},{"id":87371066,"identity":"9c3fceb3-c589-4650-8866-577b59950afd","added_by":"auto","created_at":"2025-07-23 07:09:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67384,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of cytokines, chemokines and other biomarkers secreted by WNV-infected human cerebral organoids depending on their morphology and course of infection. \u003c/strong\u003e\u0026nbsp;Screening of supernatants of WNV-infected human cerebral organoids for cytokines, \u0026nbsp;chemokines and diverse biomarkers until 14 dpi using a bead-based LegendPlexTM assay. \u0026nbsp;Organoids were subgrouped upon morphological identification of choroid plexus structures \u0026nbsp;into choroid plexus (ChP) organoids, leaving all other regional identities that could not be \u0026nbsp;identified by morphological features in the group without choroid plexus structures (Cerorganoid). Further subgrouping upon the course of WNV replication has Type A representing \u0026nbsp;organoids with a peak in virus titer until 4 dpi, while Type B represents organoids with a later \u0026nbsp;peak in virus titer until 14 dpi. Data shown represents the median value of the respective \u0026nbsp;protein. Values are normalized according to a scale with 0 representing the lowest overall \u0026nbsp;detected concentration and 100 representing the highest overall detected concentration of \u0026nbsp;the respective protein and visualized as indicated by the legend. C-C motif chemokine 17 \u0026nbsp;(CCL17). C-C motif chemokine 2 (CCL2). C-X3-C motif chemokine 1 (CX3CL1). C-X-C motif \u0026nbsp;chemokine 10 (CXCL10). Beta nerve growth factor (β-NGF). Brain-derived neurotropic factor (BDNF). Interleukin 1 receptor antagonist protein (IL-1RA). Interleukin 6 (IL-6). Interleukin 18 \u0026nbsp;(IL-18). Soluble receptor for advanced glycosylation end products (sRAGE). Soluble triggering \u0026nbsp;receptor expressed on myeloid cells 1 (sTREM-1). Soluble triggering receptor expressed on \u0026nbsp;myeloid cells 2 (sTREM-2). Tumor necrosis factor alpha (TNF-α). Vascular endothelial growth \u0026nbsp;factor (VEGF). Visinin-like protein 1 (VILIP-1).\u003c/p\u003e","description":"","filename":"Figure5markersnormalizedheatmap.png","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/453e2a82f0e0cb3e48b4e437.png"},{"id":104379350,"identity":"8daca579-574c-4b49-9761-2b55d2b5f529","added_by":"auto","created_at":"2026-03-11 07:12:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1212841,"visible":true,"origin":"","legend":"Article File","description":"","filename":"AhumancerebralorganoidmodelofWestNilevirusencephalitisshowsinnateimmunocompetency.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1_covered_0b0fba56-3046-48b4-92b2-87be99384f2a.pdf"},{"id":87371082,"identity":"39ffe3fa-6477-41ce-8944-c2d67008f4af","added_by":"auto","created_at":"2025-07-23 07:09:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":514565,"visible":true,"origin":"","legend":"Supplementary Figure 1","description":"","filename":"SupplementaryFigure1cytokineschemokines.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/28039e8a40ac7a562d2006bf.pdf"},{"id":87371083,"identity":"f5963cd7-a1ad-4b43-afa7-5a0d464ba1c3","added_by":"auto","created_at":"2025-07-23 07:09:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":626948,"visible":true,"origin":"","legend":"Supplementary Figure 2","description":"","filename":"SupplementaryFigure2otherbiomarkers.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/7b23b1a732132866bd2c91ce.pdf"},{"id":87371048,"identity":"e83f5e49-57ef-490b-a272-e727ec6475b0","added_by":"auto","created_at":"2025-07-23 07:09:02","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":274939,"visible":true,"origin":"","legend":"Supplementary Figure 3","description":"","filename":"SupplementaryFigure3longtermcytokineschemokines.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/ac25b98c77c837a8ac2d307a.pdf"},{"id":87371078,"identity":"84a135b3-f5f3-4824-a3e7-70b41e45c896","added_by":"auto","created_at":"2025-07-23 07:09:05","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":317656,"visible":true,"origin":"","legend":"Supplementary Figure 4","description":"","filename":"SupplementaryFigure4longtermotherbiomarkers.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/d28e45d417544efc7edb564a.pdf"},{"id":87371076,"identity":"69ec443d-7441-4c87-a8d6-f14578d73dfb","added_by":"auto","created_at":"2025-07-23 07:09:05","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":705343,"visible":true,"origin":"","legend":"Supplementary Figure 5","description":"","filename":"SupplementaryFigure5groupscytokines.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/593260d89f919d9a634f92d2.pdf"},{"id":87371079,"identity":"cdf06ae8-c690-4a8b-8edc-45701211643a","added_by":"auto","created_at":"2025-07-23 07:09:05","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":791289,"visible":true,"origin":"","legend":"Supplementary Figure 6","description":"","filename":"SupplementaryFigure6groupschemokines.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6975922/v1/7237147bd1e9e2356894205c.pdf"},{"id":87371080,"identity":"5aef682e-3ad0-481d-ad77-0b0baeffd009","added_by":"auto","created_at":"2025-07-23 07:09:05","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":903421,"visible":true,"origin":"","legend":"Supplementary Figure 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immunocompetency","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-6975922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6975922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"West Nile virus (WNV), an arbovirus of emerging global interest, can cause neuroinvasive disease in humans. Currently, no protective vaccine or specific treatment is available for human WNV encephalitis. The virus induces neuronal cell death, while astrocytes and microglia, cells important in the antiviral defense of the central nervous system, are suspected to contribute to WNV pathology. Hence, understanding their role is crucial for future treatment approaches. However, human data is limited, and animal models as well as in vitro monocultures have inherent limitations. In this study, human cerebral organoids forming complex 3D in vitro structures including neurons, astrocytes and microglia were used as a novel WNV encephalitis model. Exposure of 100-day-old cerebral organoids to WNV resulted in robust infection leading to heterogenous courses. An early strong viral replication was shown to potentially result in viral clearance, while a late peak resulted in more long-term infection. Viral foci were seen in cortical-like areas, rich in neurons and astrocytes, however void of microglia. Pro-inflammatory cytokines (IL-6, TNF-α, IL-18), chemokines (CXCL10, CCL17, CX3CL1, CCL2) and biomarkers (IL-1RA, sTREM-1, sRAGE, BDNF) were increasingly released. Conclusively, human cerebral organoids make suitable novel WNV encephalitis models with outstanding properties to study acute and long-term infection.","manuscriptTitle":"A human cerebral organoid model of West Nile virus encephalitis shows innate immunocompetency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 07:08:36","doi":"10.21203/rs.3.rs-6975922/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":"c2010db4-c75e-4f2e-8bd4-bdc0e8f0e521","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51878904,"name":"Biological sciences/Immunology/Innate immunity"},{"id":51878905,"name":"Biological sciences/Microbiology/Virology/West nile virus"}],"tags":[],"updatedAt":"2026-03-11T07:10:50+00:00","versionOfRecord":{"articleIdentity":"rs-6975922","link":"https://doi.org/10.1038/s41467-026-70281-x","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2026-03-07 05:00:00","publishedOnDateReadable":"March 7th, 2026"},"versionCreatedAt":"2025-07-23 07:08:36","video":"","vorDoi":"10.1038/s41467-026-70281-x","vorDoiUrl":"https://doi.org/10.1038/s41467-026-70281-x","workflowStages":[]},"version":"v1","identity":"rs-6975922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6975922","identity":"rs-6975922","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}