Human-relevant coronavirus research: Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework- the CIAO Project

By Rebecca Ram

As we approach the end of 2021 (and almost two years since the pandemic began) an innovative project continues to investigate the biological mechanisms underlying COVID-19, using the ground breaking concept of Adverse Outcome Pathways (AOPs).

Launched in May 2020, the CIAO project (Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework) has involved the collaboration of scientific experts across many disciplines including (but not limited to) molecular biology, virology, toxicology, immunology and clinical research. I was pleased to contribute to the project during late 2020 and early 2021.

The AOP is a concept which maps a specific pathway to provide highly mechanistic information on the effects of a ‘stressor’, beginning with ‘molecular initiating events’ (MIEs) and progressing through higher level ‘key events’ (KEs) at cell, organ and tissue level, through to adverse outcomes observed in the individual and ultimately populations.

The AOP concept was originally developed to establish pathways of toxicological responses to chemicals as stressors, but as diseases, bacteria and viruses can act in a similar way to trigger MIEs, AOPs have far broader application beyond chemical safety into the pathogenesis of disease. Key events and adverse outcomes are not necessarily unique to one AOP and so can be connected to form adverse outcome ‘networks’.

Image reproduced from: Nymark P, Sachana M, Leite SB, Sund J, Krebs CE, Sullivan K, Edwards S, Viviani L, Willett C, Landesmann B and Wittwehr C (2021) Systematic Organization of COVID-19 Data Supported by the Adverse Outcome Pathway Framework. Front. Public Health 9:638605. doi: 10.3389/fpubh.2021.638605

Therefore, the CIAO project is reviewing and organising the ‘big data’ available on the key events involved in the body’s response to the SARS-CoV-2 virus, also making use of extensive research on related coronaviruses (e.g. SARS-CoV-1). Expert working groups collaborate on an ongoing basis and four comprehensive workshops have been held to date, with a number of modelling outcomes in progress, including for example acute respiratory distress, lung fibrosis, neurological, liver and cardiovascular injury.  These are very top-level descriptions and much more detail on the achievements of the project so far, as well as publications are available on the CIAO website.

To find out much more including how to join the CIAO project, visit

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