Hypertension uncouples SARS-CoV-2 viral burden from lung injury through dysregulated host responses

Hypertension uncouples SARS-CoV-2 viral burden from lung injury through dysregulated host responses | 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 Hypertension uncouples SARS-CoV-2 viral burden from lung injury through dysregulated host responses Stephen Barr, Khandaker Fariha, Xiangru Lu, Nicole Friesen, Qingping Feng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8998153/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Hypertension is among the strongest risk factors for severe COVID-19, yet the mechanisms by which pre-existing vascular dysfunction reshapes host responses to SARS-CoV-2 remain incompletely defined. Here we establish a physiologically relevant, infection-permissive hypertensive golden Syrian hamster model using chronic nitric oxide synthase inhibition that induces sustained blood pressure elevation with concentric cardiac remodeling and preserved systolic function. Following SARS-CoV-2 challenge, hypertensive animals develop accelerated and exacerbated diffuse alveolar damage characterized by amplified vascular injury, thrombosis, hemorrhage, and inflammatory infiltration. This heightened pathology occurs despite equivalent pulmonary viral RNA levels and infectious titers compared to normotensive controls, demonstrating a dissociation between viral burden and disease severity. Mechanistically, hypertension amplifies early induction of TNF-α and IL-1β, selective endothelial activation, delayed type I and II interferon responses, and transient metabolic derangements including bicarbonate deficit and stress hyperglycemia. These findings position hypertension as a determinant of host-pathology uncoupled from viral replication and provide a scalable, infection-permissive platform to evaluate vascular and immunomodulatory interventions for COVID-19 and future respiratory viral threats. Health sciences/Diseases/Cardiovascular diseases/Hypertension Biological sciences/Microbiology/Virology/SARS-CoV-2 hypertension L-NAME golden Syrian hamster SARS-CoV-2 COVID-19 cardiovascular function comorbidity cytokine dysregulation host-pathogen interactions translational model endothelial dysfunction immunometabolic reprogramming. Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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-8998153","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":599521934,"identity":"cf840f8a-07d8-4cbe-b324-964fa4a64706","order_by":0,"name":"Stephen Barr","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYJACZhBhACI+EKWeDUkL4wyStTDzEKNDfn7zsccFFXcYzNnPPvts23ZYjoH98AO8WgyOsaUbzzjzjMGyJ914dm7bYWMGnjQD/FrYeMykedsOMxgcSGNmzm27ndggwYBfi3wb/zdp3n9ALeefMTNbgrWwEwi4Yzxs0rwNQC03gLYwgrXwEHDYsTRzY55jh3ksZzxjZuw599+YjSenAL/Dmg8/e8xTc1jOnD+NmeFHWZocP/vxDfgdBo4ZBgYeVC4xWkbBKBgFo2AU4AYAuYE8lIL3PLcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0028-7430","institution":"Western University","correspondingAuthor":true,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Barr","suffix":""},{"id":599521935,"identity":"f6c24e16-af84-42af-92c5-c7eb9e70f6eb","order_by":1,"name":"Khandaker Fariha","email":"","orcid":"","institution":"Western University","correspondingAuthor":false,"prefix":"","firstName":"Khandaker","middleName":"","lastName":"Fariha","suffix":""},{"id":599521936,"identity":"77efdebb-4379-4598-853b-a26619ce4d7d","order_by":2,"name":"Xiangru Lu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Xiangru","middleName":"","lastName":"Lu","suffix":""},{"id":599521937,"identity":"3bafb7b2-487e-4330-b36d-12b0376f1d18","order_by":3,"name":"Nicole Friesen","email":"","orcid":"","institution":"Western University","correspondingAuthor":false,"prefix":"","firstName":"Nicole","middleName":"","lastName":"Friesen","suffix":""},{"id":599521938,"identity":"071c73f7-dd5c-4184-a56c-f168bea9bc0f","order_by":4,"name":"Qingping Feng","email":"","orcid":"https://orcid.org/0000-0001-9739-2765","institution":"University of Western Ontario","correspondingAuthor":false,"prefix":"","firstName":"Qingping","middleName":"","lastName":"Feng","suffix":""}],"badges":[],"createdAt":"2026-02-28 22:25:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8998153/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8998153/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104403040,"identity":"8b4c4b1a-e86c-4a39-a883-d7d1acba4c2c","added_by":"auto","created_at":"2026-03-11 12:17:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1809193,"visible":true,"origin":"","legend":"Article File","description":"","filename":"FarihaetalManuscriptvTextandFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8998153/v1_covered_72d49391-3a36-4a7d-91bd-bd20f00f6ae4.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Hypertension uncouples SARS-CoV-2 viral burden from lung injury through dysregulated host responses","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"hypertension, L-NAME, golden Syrian hamster, SARS-CoV-2, COVID-19, cardiovascular function, comorbidity, cytokine dysregulation, host-pathogen interactions, translational model, endothelial dysfunction, immunometabolic reprogramming.","lastPublishedDoi":"10.21203/rs.3.rs-8998153/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8998153/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Hypertension is among the strongest risk factors for severe COVID-19, yet the mechanisms by which pre-existing vascular dysfunction reshapes host responses to SARS-CoV-2 remain incompletely defined. 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