{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:34:03Z","timestamp":1768455243412,"version":"3.49.0"},"reference-count":95,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["335524"],"award-info":[{"award-number":["335524"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["21027"],"award-info":[{"award-number":["21027"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Eastern Finland","award":["335524"],"award-info":[{"award-number":["335524"]}]},{"name":"University of Eastern Finland","award":["21027"],"award-info":[{"award-number":["21027"]}]},{"name":"European Commission, Joint Research Centre (JRC)","award":["335524"],"award-info":[{"award-number":["335524"]}]},{"name":"European Commission, Joint Research Centre (JRC)","award":["21027"],"award-info":[{"award-number":["21027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have investigated the mechanisms leading to anosmia in COVID-19; however, the evidence is scattered, and the mechanisms remain poorly understood. Based on a comprehensive review of the literature, we aim here to evaluate the current knowledge and uncertainties regarding the mechanisms leading to short-term anosmia following SARS-CoV-2 infection. We applied an adverse outcome pathway (AOP) framework, well established in toxicology, to propose a sequence of measurable key events (KEs) leading to short-term anosmia in COVID-19. Those KEs are (1) SARS-CoV-2 Spike proteins binding to ACE-2 expressed by the sustentacular (SUS) cells in the olfactory epithelium (OE); (2) viral entry into SUS cells; (3) viral replication in the SUS cells; (4) SUS cell death; (5) damage to the olfactory sensory neurons and the olfactory epithelium (OE). This AOP-aligned approach allows for the identification of gaps where more research should be conducted and where therapeutic intervention could act. Finally, this AOP gives a frame to explain several disease features and can be linked to specific factors that lead to interindividual differences in response to SARS-CoV-2 infection.<\/jats:p>","DOI":"10.3390\/cells11193027","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T21:23:27Z","timestamp":1664313807000},"page":"3027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mechanistic Understanding of the Olfactory Neuroepithelium Involvement Leading to Short-Term Anosmia in COVID-19 Using the Adverse Outcome Pathway Framework"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-6792","authenticated-orcid":false,"given":"Muhammad Ali","family":"Shahbaz","sequence":"first","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"De Bernardi","sequence":"additional","affiliation":[{"name":"Division of Otorhinolaryngology, Department of Biotechnologies and Life Sciences, University of Insubria, Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arto","family":"Alatalo","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalini","family":"Sachana","sequence":"additional","affiliation":[{"name":"Environment Health and Safety Division, Environment Directorate, Organisation for Economic Cooperation and Development (OECD), 75775 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-482X","authenticated-orcid":false,"given":"Laure-Alix","family":"Clerbaux","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amalia","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surat","family":"Parvatam","sequence":"additional","affiliation":[{"name":"Centre for Predictive Human Model Systems, Atal Incubation Centre-Centre for Cellular and Molecular Biology (AIC-CCMB), Habsiguda, Hyderabad 500039, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Landesmann","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-8589","authenticated-orcid":false,"given":"Katja M.","family":"Kanninen","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2773-6408","authenticated-orcid":false,"given":"Sandra","family":"Coecke","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","unstructured":"OECD (2017). Guidance Document for the Use of Adverse Outcome Pathways in Developing Integrated Approaches to Testing and Assessment (IATA), OECD."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.yrtph.2014.09.009","article-title":"Applying Adverse Outcome Pathways (AOPs) to Support Integrated Approaches to Testing and Assessment (IATA)","volume":"70","author":"Tollefsen","year":"2014","journal-title":"Regul. 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