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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>Influenza A viruses (IAVs) pose a threat to human health. Although receptor specificity, polymerase adaptation, and airway tropism have been studied extensively, it remains unresolved how they combine to shape tropism in airway epithelia. Here, we show that avian IAVs infect ciliated and secretory cells but preferentially bind to ciliated cells because of higher apical \u03b12,3-linked sialic acid levels. As replication levels are comparable between cell types, this translates into overall preference for ciliated cells. Human IAVs also preferentially bind to ciliated cells despite comparable \u03b12,6-linked sialic acid abundance. Instead, they show higher viral RNA and protein levels in secretory cells, linked to their compatibility with human ANP32 proteins and modestly higher ANP32A\/B expression in this cell type, resulting in equal infection levels across cell types. Our findings redefine IAV tropism in the human airway as a stage-resolved process shaped by the interplay between apical glycans, viral binding, polymerase cofactor compatibility, and cell-type\u2013specific replication capacity, moving beyond receptor-centric models.<\/jats:p>","DOI":"10.1126\/sciadv.aei5782","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:58:42Z","timestamp":1792778322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Opposing cell-type preferences for binding and replication shape influenza A virus infection in human airways"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4404-4509","authenticated-orcid":true,"given":"Josephine","family":"von Kempis","sequence":"first","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9876-3836","authenticated-orcid":true,"given":"Marie O.","family":"Pohl","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6524-9233","authenticated-orcid":true,"given":"Elisabeth","family":"Gaggioli","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7081-4119","authenticated-orcid":true,"given":"Cyrille","family":"Niklaus","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1013-876X","authenticated-orcid":true,"given":"Alexandra","family":"Trkola","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3111-5954","authenticated-orcid":true,"given":"Geert-Jan","family":"Boons","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands."},{"name":"Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1586-4464","authenticated-orcid":true,"given":"Robert P.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9491-2892","authenticated-orcid":true,"given":"Silke","family":"Stertz","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2008.04.011"},{"key":"e_1_3_2_3_2","unstructured":"World Health Organization Influenza (seasonal) (2025). www.who.int\/news-room\/fact-sheets\/detail\/influenza-(seasonal)."},{"key":"e_1_3_2_4_2","first-page":"377","article-title":"Influenza A virus reassortment","volume":"385","author":"Steel J.","year":"2014","unstructured":"J. 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