{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:51:06Z","timestamp":1793677866904,"version":"4.5.1"},"reference-count":142,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'universit\u00e0 e della ricerca","doi-asserted-by":"crossref","award":["PNRR-Spoke 13-CUP-G43C2200260007-INF-ACT"],"award-info":[{"award-number":["PNRR-Spoke 13-CUP-G43C2200260007-INF-ACT"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Respiratory viral co-infections by viruses such as influenza virus, SARS-CoV-2, and respiratory syncytial virus (RSV) are a significant clinical issue in high-risk populations such as children, elderly patients, and immunocompromised individuals. Sequential and simultaneous co-infections exacerbate disease severity, leading to acute respiratory distress syndrome (ARDS), prolonged hospitalization, and increased mortality. Molecular and immunological interactions are complex, context-dependent, and largely unknown. Experimental models of infection that accurately mimic human respiratory physiology are required for the study of viral dynamics, virus\u2013virus interactions, and virus\u2013host interactions. This review outlines a range of complex in vitro and ex vivo models, including organoids, air\u2013liquid interface cultures, lung-on-a-chip platforms, and in vivo animal models, highlighting their ability to simulate the complexity of respiratory co-infections and their limitations. The field has developed significantly, despite challenges like variability across viral strains, timing of infection, and non-standardization of models. Integration of multi-omics technologies and application of highly translational models such as non-human primates and lung-on-a-chip technology are promising avenues to uncover the molecular determinants of co-infection and guide development of targeted therapeutic strategies. Interrelatedness of experimental models and clinical outcomes is highly critical to improve prevention and treatment of respiratory viral co-infections mainly among high-risk populations.<\/jats:p>","DOI":"10.3390\/microorganisms13112444","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T02:50:48Z","timestamp":1761533448000},"page":"2444","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Experimental Models to Investigate Viral and Cellular Dynamics in Respiratory Viral Co-Infections"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8956-3224","authenticated-orcid":false,"given":"Ozge","family":"Yazici","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-6675","authenticated-orcid":false,"given":"Claudia","family":"Vanetti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-6191","authenticated-orcid":false,"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"},{"name":"IRCCS Fondazione Don Carlo Gnocchi, 20148 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-4235","authenticated-orcid":false,"given":"Mara","family":"Biasin","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.immuni.2020.05.004","article-title":"Respiratory Virus Infections: Understanding COVID-19","volume":"52","author":"Subbarao","year":"2020","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/jmv.25674","article-title":"Recent Advances in the Detection of Respiratory Virus Infection in Humans","volume":"92","author":"Zhang","year":"2020","journal-title":"J. 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