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AORBs exhibit a spatio-temporally stable apical-out morphology, facilitating high-yield direct intact-organoid virus infection. Single-cell RNA sequencing and immunohistochemistry confirm the physiologically relevant recapitulation of differentiated human airway epithelia. The cellular tropism of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains along with host response differences between Delta, Washington, and Omicron variants, as observed in transcriptomic profiles, also suggest clinical relevance. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds (remdesivir, bemnifosbuvir, and nirmatrelvir) demonstrates that AORBs efficiently predict human efficacy, comparable to gold-standard air-liquid interface cultures, but with higher throughput (\u223c10-fold) and fewer cells (\u223c100-fold). This combination of throughput and relevance allows AORBs to robustly detect false negative results in efficacy, preventing irretrievable loss of promising lead compounds. While this work leverages the SARS-CoV-2 study as a proof-of-concept application, the standardization capacity of AORB holds broader implications in line with regulatory efforts to push alternatives to animal studies.\n                <\/jats:p>","DOI":"10.1101\/2024.01.02.573939","type":"posted-content","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T11:11:36Z","timestamp":1704453096000},"source":"Crossref","is-referenced-by-count":9,"title":["Development of robust antiviral assays using relevant apical-out human airway organoids"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-3885","authenticated-orcid":false,"given":"Ji-Hoon","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0056-176X","authenticated-orcid":false,"given":"Julia C.","family":"LeCher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7533-2558","authenticated-orcid":false,"given":"Eric","family":"Parigoris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9658-7667","authenticated-orcid":false,"given":"Noriyuki","family":"Shinagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8721-8744","authenticated-orcid":false,"given":"Jason","family":"Sentosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7786-7444","authenticated-orcid":false,"given":"Candela","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8575-6103","authenticated-orcid":false,"given":"Shu Ling","family":"Goh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5534-0705","authenticated-orcid":false,"given":"Ramyani","family":"De","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9728-5038","authenticated-orcid":false,"given":"Keivan","family":"Zandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Amblard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-3354","authenticated-orcid":false,"given":"Eric J.","family":"Sorscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-3992","authenticated-orcid":false,"given":"Jason R.","family":"Spence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3526-9985","authenticated-orcid":false,"given":"Rabindra","family":"Tirouvanziam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-3614","authenticated-orcid":false,"given":"Raymond F.","family":"Schinazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4385-9080","authenticated-orcid":false,"given":"Shuichi","family":"Takayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024071500150473000_2024.01.02.573939v2.1","doi-asserted-by":"publisher","DOI":"10.3791\/55159"},{"key":"2024071500150473000_2024.01.02.573939v2.2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.11.5654-5666.2002"},{"key":"2024071500150473000_2024.01.02.573939v2.3","doi-asserted-by":"crossref","first-page":"5542","DOI":"10.1128\/jvi.66.9.5542-5552.1992","article-title":"Expression of the influenza A virus M2 protein is restricted to apical surfaces of polarized epithelial cells","volume":"66","year":"1992","journal-title":"J. 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