Circadian misalignment potentiates blood-brain barrier disruption and mitochondria dysregulation in Zika virus infection

Circadian misalignment potentiates blood-brain barrier disruption and mitochondria dysregulation in Zika virus infection | 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 Research Article Circadian misalignment potentiates blood-brain barrier disruption and mitochondria dysregulation in Zika virus infection Timea Teglas, Silvia Torices, Anne Caroline Marcos, Bogusława Orzechowska-Wylęgała, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6298126/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jun, 2025 Read the published version in Fluids and Barriers of the CNS → Version 1 posted 8 You are reading this latest preprint version Abstract Background : Zika virus (ZIKV) is a mosquito-borne Flavivirus with a strong affinity for the central nervous system (CNS). After infection, ZIKV can cross the blood-brain barrier (BBB) and reach the CNS, causing potential harm to both adult and developing brains. Methods : The current study aims to evaluate how dysregulated circadian rhythms can affect brain infection by ZIKV, as biorhythms regulate essential physiological processes and disrupted circadian clock can contribute to the pathogenesis of multiple disorders. Both ZIKV infection and circadian rhythm alterations have been related to the disruption of the BBB integrity by modulating the expression of the tight junction (TJ) proteins, however, the input of circadian misalignment on ZIKV infection has never been studied in the literature. Results : Infection of brain endothelial cells with ZIKV selectively impacted endothelial permeability and dysregulated the expression of TJ and mitochondrial proteins. Importantly, these effects were potentiated by silencing Bmal1, a critical circadian rhythm gene. These results were then confirmed in vivo in Bmal1 endothelial cell-specific knockout mice, which were infected with ZIKV at 105 PFU (plaque-forming unit) by retro-orbital infusion. ZIKV infection resulted in a marked decrease in claudin-5, occludin, JAM-3, and ZO-1 expression levels in these mice. In addition, ZIKV affected the expression of FIS1 protein levels and the respiratory complexes of II, III, and IV in mice lacking Bmal1 expression in endothelial cells. Conclusions : Findings from this study contribute to a better understanding of the impact of circadian misalignment on the pathology of ZIKV infection in the adult brain. Zika virus blood-brain barrier tight junctions mitochondria circadian rhythm Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 16 Jun, 2025 Read the published version in Fluids and Barriers of the CNS → Version 1 posted Editorial decision: Revision requested 07 May, 2025 Reviews received at journal 28 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 01 Apr, 2025 Editor assigned by journal 28 Mar, 2025 Submission checks completed at journal 28 Mar, 2025 First submitted to journal 24 Mar, 2025 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. 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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-6298126","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":441730184,"identity":"82680ade-f7c8-4554-b951-071fbe16af7f","order_by":0,"name":"Timea Teglas","email":"","orcid":"","institution":"University of Miami","correspondingAuthor":false,"prefix":"","firstName":"Timea","middleName":"","lastName":"Teglas","suffix":""},{"id":441730186,"identity":"69b57eb8-b794-486e-974c-dfb6b7fc97e8","order_by":1,"name":"Silvia Torices","email":"","orcid":"","institution":"University of Miami","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Torices","suffix":""},{"id":441730187,"identity":"b15a5712-c414-4591-8364-9fb04f13f664","order_by":2,"name":"Anne Caroline Marcos","email":"","orcid":"","institution":"University of Miami","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"Caroline","lastName":"Marcos","suffix":""},{"id":441730188,"identity":"e06b4c1b-c5b0-4d04-8cd3-69aad908ceb0","order_by":3,"name":"Bogusława Orzechowska-Wylęgała","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Bogusława","middleName":"","lastName":"Orzechowska-Wylęgała","suffix":""},{"id":441730189,"identity":"cd7a3abe-d34b-4e5e-be81-6a9cc789e16c","order_by":4,"name":"Michal Toborek","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYHACNhBhwA8kJMCIGcjiwa8BokWygWQtBgfA6qEAnxbd+c3HHnzcY2NsfO3wwRuMORbyuu0MjA/etuHWYnaMLd1wxrM0M7PbackWjNskDLcdZmA2nItXC4+ZNM+BwzZmt3PMJIBaGIFa2KR5CWv5b2M8O/8bSIs9UAv7byK0HDAzkM5hA2lJBNnCjF9LGtAvB5KNJW6nGVskbpNI3naYsVlyzjk8Wg4fPvbgwwE7w/7ZyQ9vfNxWZ7vt/OGDH96U4daCChLAJGMDsepHwSgYBaNgFOAAAIjPTczjW//sAAAAAElFTkSuQmCC","orcid":"","institution":"University of Miami","correspondingAuthor":true,"prefix":"","firstName":"Michal","middleName":"","lastName":"Toborek","suffix":""}],"badges":[],"createdAt":"2025-03-24 20:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6298126/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6298126/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12987-025-00669-2","type":"published","date":"2025-06-16T15:57:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85231393,"identity":"6b61d792-8d3f-47ad-a1db-46233399c70b","added_by":"auto","created_at":"2025-06-23 16:07:10","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1345280,"visible":true,"origin":"","legend":"","description":"","filename":"TeglasetalFBCNS2025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6298126/v1_covered_f065bf74-bee7-4e62-a667-5b0f38afdaf8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Circadian misalignment potentiates blood-brain barrier disruption and mitochondria dysregulation in Zika virus infection","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"fluids-and-barriers-of-the-cns","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fbcn","sideBox":"Learn more about [Fluids and Barriers of the CNS](http://fluidsbarrierscns.biomedcentral.com/)","snPcode":"12987","submissionUrl":"https://submission.nature.com/new-submission/12987/3","title":"Fluids and Barriers of the CNS","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Zika virus, blood-brain barrier, tight junctions, mitochondria, circadian rhythm","lastPublishedDoi":"10.21203/rs.3.rs-6298126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6298126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Zika virus (ZIKV) is a mosquito-borne Flavivirus with a strong affinity for the central nervous system (CNS). After infection, ZIKV can cross the blood-brain barrier (BBB) and reach the CNS, causing potential harm to both adult and developing brains.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The current study aims to evaluate how dysregulated circadian rhythms can affect brain infection by ZIKV, as biorhythms regulate essential physiological processes and disrupted circadian clock can contribute to the pathogenesis of multiple disorders. 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