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This study establishes human airway organoids as a robust model for investigating BSL-4 pathogens. In contrast to conventional cell lines, airway organoids enable investigation of virus-host interactions within a human tissue context, providing insights that are more directly translatable to human disease. We generated airway organoids from both clinical donor tissues and commercially available nasal epithelial cells and showed in comparative analyses with whole lung tissue that these organoids are comparable in terms of cell composition. Despite biological variations, airway organoids derived from different sources and donors exhibit a remarkably similar cellular make-up. We further demonstrated that organoids derived from nasal swabs can effectively replicate BSL-4 viruses. This establishes them as a standardized 3D model for broader research applications including infection kinetics, immune evasion, and tissue-specific tropism within a controlled environment. This platform provides a powerful tool for antiviral testing and studying virus-host interactions, thus helping bridge critical gaps in high containment virus research and advancing our understanding of these pathogens, bypassing some of the challenges of animal models.<\/jats:p>","DOI":"10.1038\/s41598-026-45813-6","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T16:04:43Z","timestamp":1774627483000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human airway organoids as a versatile model to study BSL-4 virus replication and pathogenesis"],"prefix":"10.1038","volume":"16","author":[{"given":"Joo-Hee","family":"W\u00e4lzlein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Reusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Ospina-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Olmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura V.","family":"Klotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Klotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susann","family":"Kummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"45813_CR1","unstructured":"Ebola Situation Report\u2009\u2013\u200930 March 2016, (2016). https:\/\/reliefweb.int\/report\/sierra-leone\/who-ebola-situation-report-30-march-2016"},{"key":"45813_CR2","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41578-021-00279-y","volume":"6","author":"M Hofer","year":"2021","unstructured":"Hofer, M. & Lutolf, M. 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