Organoid modeling of lung-resident immune responses to SARS-CoV-2 infection

Organoid modeling of lung-resident immune responses to SARS-CoV-2 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 Biological Sciences - Article Organoid modeling of lung-resident immune responses to SARS-CoV-2 infection Joseph Rathkey, Shannon Choi, Vincent van Unen, Huimin Zhang, and 33 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2870695/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Tissue-resident immunity mediates host defense against pathogens and enables rapid adaptive memory responses. However, the study of tissue-resident immunity is hindered by a singular lack of experimental systems allowing pathogenic epithelial infection amidst the full spectrum of endogenous immune subsets. Particularly in lung, differing notions of transient versus sustained residency of tissue-resident memory T cells (TRM) have questioned the extent to which recall immunity to respiratory pathogens occurs locally or in concert with secondary lymphoid organs. We thus generated long-term adult human distal lung organoids from intact tissue fragments in 3D air-liquid interface (ALI) culture that co-preserved epithelial and stromal architecture alongside endogenous lung-resident immune cells (T, B, NK, myeloid). The organoid T cells exhibited persistent cytokine-assisted maintenance, expressed residency and memory markers, and preserved T cell receptor (TCR) repertoires of cognate fresh tissue. SARS-CoV-2 vigorously infected the organoid lung epithelium, stimulated inflammatory cytokine production, and crucially, induced widespread SARS-CoV-2-specific, tissue-resident T cell responses. Our studies introduce a robust adult human lung organoid experimental system containing a physiologic air interface and diverse resident immune subsets, demonstrate the organ-autonomous sufficiency of lung pathogen memory T cell responses, distinct from secondary lymphoid tissue, and provide a platform to investigate tissue-resident immunity in health and disease. Biological sciences/Biological techniques/Biological models/Respiratory system models Biological sciences/Immunology/Infectious diseases/Viral infection Full Text Additional Declarations The authors declare potential competing interests as follows: C.J.K. and S.S.C. are listed as inventors on provisional patent PCT/US2022/029869 describing the methods in this paper. C.J.K. is a founder of Surrozen, Inc. C.J.K. and M.M.D. are founders of Mozart Therapeutics and NextVivo, Inc. All other authors declare no competing interests. Supplementary Files 20260206SupplementaryInformationGuide.pdf Supplementary Information Guide 20260206SupplementaryFiles.xlsx Supplementary Files 20260206ExtendedData.pdf Extended Data Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-2870695","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":587133237,"identity":"5e6c1514-a604-4b5c-8d43-a9971e0a7b09","order_by":0,"name":"Joseph Rathkey","email":"","orcid":"https://orcid.org/0009-0004-5981-7469","institution":"Stanford University","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Rathkey","suffix":""},{"id":197609739,"identity":"07c7330a-296e-4bf7-9597-c2e76ac470f3","order_by":1,"name":"Shannon Choi","email":"","orcid":"","institution":"Stanford 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