Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework

Laure Alix Clerbaux, Maria Cristina Albertini, Núria Amigó, Anna Beronius, Gillina F.G. Bezemer, Sandra Coecke, Evangelos P. Daskalopoulos, Giusy del Giudice, Dario Greco, Lucia Grenga, Alberto Mantovani, Amalia Muñoz, Elma Omeragic, Nikolaos Parissis, Mauro Petrillo, Laura A. Saarimäki, Helena Soares, Kristie Sullivan, Brigitte Landesmann

Research output: Contribution to journalReview articlepeer-review

17 Citations (Scopus)
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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.

Original languageEnglish
Article number4464
JournalJournal of Clinical Medicine
Issue number15
Publication statusPublished - Aug 2022


  • adverse outcome pathway
  • age
  • co-morbidities
  • COVID-19
  • environment
  • lifestyle
  • modulating factors
  • pre-existing conditions
  • SARS-CoV-2 infection
  • sex


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