{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T15:36:27Z","timestamp":1781624187911,"version":"3.54.5"},"reference-count":570,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"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":["322761"],"award-info":[{"award-number":["322761"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["CEECIND\/01049\/2020"],"award-info":[{"award-number":["CEECIND\/01049\/2020"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["322761"],"award-info":[{"award-number":["322761"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["CEECIND\/01049\/2020"],"award-info":[{"award-number":["CEECIND\/01049\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.<\/jats:p>","DOI":"10.3390\/jcm11154464","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T02:06:42Z","timestamp":1659319602000},"page":"4464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-482X","authenticated-orcid":false,"given":"Laure-Alix","family":"Clerbaux","sequence":"first","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-1475","authenticated-orcid":false,"given":"Maria Cristina","family":"Albertini","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0116-9145","authenticated-orcid":false,"given":"N\u00faria","family":"Amig\u00f3","sequence":"additional","affiliation":[{"name":"Biosfer Teslab SL., 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Universitat Rovira i Virgili (URV), 23204 Reus, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9494-5395","authenticated-orcid":false,"given":"Anna","family":"Beronius","sequence":"additional","affiliation":[{"name":"Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillina F. G.","family":"Bezemer","sequence":"additional","affiliation":[{"name":"Impact Station, 1223 JR Hilversum, The Netherlands"},{"name":"Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Coecke","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos P.","family":"Daskalopoulos","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"del Giudice","sequence":"additional","affiliation":[{"name":"Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9195-9003","authenticated-orcid":false,"given":"Dario","family":"Greco","sequence":"additional","affiliation":[{"name":"Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5560-1717","authenticated-orcid":false,"given":"Lucia","family":"Grenga","sequence":"additional","affiliation":[{"name":"D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, SPI, F-30200 Bagnols-sur-Ceze, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5996-4926","authenticated-orcid":false,"given":"Elma","family":"Omeragic","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-0885","authenticated-orcid":false,"given":"Nikolaos","family":"Parissis","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-4704","authenticated-orcid":false,"given":"Mauro","family":"Petrillo","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Saarim\u00e4ki","sequence":"additional","affiliation":[{"name":"Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5881-3843","authenticated-orcid":false,"given":"Helena","family":"Soares","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology and Pathogenesis, Chronic Diseases Research Centre, Faculdade de Ci\u00eancias M\u00e9dicas Medical School, University of Lisbon, 1649-004 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristie","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Physicians Committee for Responsible Medicine, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Landesmann","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"ref_1","first-page":"157","article-title":"WHO Declares COVID-19 a Pandemic","volume":"91","author":"Cucinotta","year":"2020","journal-title":"Acta Biomed"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"638605","DOI":"10.3389\/fpubh.2021.638605","article-title":"Systematic Organization of COVID-19 Data Supported by the Adverse Outcome Pathway Framework","volume":"9","author":"Nymark","year":"2021","journal-title":"Front. 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