Sex- and Age-Dependent Neuroimmune Dysregulation and Early Neurodegenerative Signatures Following SARS-CoV-2 Infection in Golden Syrian Hamsters

Sex- and Age-Dependent Neuroimmune Dysregulation and Early Neurodegenerative Signatures Following SARS-CoV-2 Infection in Golden Syrian Hamsters | 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 Sex- and Age-Dependent Neuroimmune Dysregulation and Early Neurodegenerative Signatures Following SARS-CoV-2 Infection in Golden Syrian Hamsters Siddappa Byrareddy, Narendra Kumar, Arpan Acharya, Rajesh Das, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9130692/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Post-acute sequelae of SARS-CoV-2 infection, or Long-COVID, affects millions globally and is characterized by persistent symptoms affecting multiple organs, yet the underlying mechanisms remain poorly defined. Here, we used Golden Syrian Hamsters (GSH) infected with the SARS-CoV-2 to investigate how sex and age shape viral persistence, organ-specific pathology, immune responses, and neurological outcomes during acute infection and Long-COVID. We show that during Long-COVID, viral RNA persists only in the lungs of male hamsters. Lung pathology revealed sustained inflammation and tissue remodeling, with young females exhibiting greater fibrosis. Transcriptomic profiling across brain, lung, and heart identified pronounced sex- and age-dependent regulation of gene expression spanning immune, neuroinflammatory, and neurotransmitter signaling pathways. These transcriptomic alterations were accompanied by sex-specific behavioral changes and persistent microstructural remodeling in cognition-associated brain regions. Additionally, SARS-CoV-2 altered α-synuclein homeostasis and microglial activation alongside gut microbiome composition in a sex- and age-dependent manner. Together, our findings demonstrate that, in GSH Long-COVID is strongly modulated by sex and age, influencing viral RNA persistence, immune and neurobiological responses, and gut microbiota composition mirroring clinical outcomes reported in human cohorts. This study establishes SARS-CoV-2-infected GSH as a model for dissecting the mechanisms of Long-COVID and informing targeted prevention strategies. Biological sciences/Microbiology/Virology/SARS-CoV-2 Health sciences/Diseases/Infectious diseases/Viral infection Long-COVID PASC GSH Neuroinflammation Animal model Sex-differences Full Text Additional Declarations There is NO Competing Interest. Supplementary Files KumarNetalnrreportingsummary.pdf Nature reporting summary Supplementarymaterials.pdf Supplementary Information RNA.docx Access raw data Cite Share Download PDF Status: Posted 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-9130692","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":617439900,"identity":"6e66e06b-1341-4eb7-8496-5910ec4fc78c","order_by":0,"name":"Siddappa 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Here, we used Golden Syrian Hamsters (GSH) infected with the SARS-CoV-2 to investigate how sex and age shape viral persistence, organ-specific pathology, immune responses, and neurological outcomes during acute infection and Long-COVID. We show that during Long-COVID, viral RNA persists only in the lungs of male hamsters. Lung pathology revealed sustained inflammation and tissue remodeling, with young females exhibiting greater fibrosis. Transcriptomic profiling across brain, lung, and heart identified pronounced sex- and age-dependent regulation of gene expression spanning immune, neuroinflammatory, and neurotransmitter signaling pathways. These transcriptomic alterations were accompanied by sex-specific behavioral changes and persistent microstructural remodeling in cognition-associated brain regions. Additionally, SARS-CoV-2 altered α-synuclein homeostasis and microglial activation alongside gut microbiome composition in a sex- and age-dependent manner. 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