COVID-19 through Adverse Outcome Pathways: Building networks to better understand the disease - 3rd CIAO AOP Design Workshop

Abstract

On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project “Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework” aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and posi­tioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowd­sourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, inte­grating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd.

Keywords: COVID-19; adverse outcome pathway; interdisciplinarity.

Fig. 1:

Schematic representation of the COVID-19 AOP network built on Hub KEs (ACE2 binding, viral entry, coronavirus production and ACE2 dysregulation) and Hub AOPs (hyperinflammation and coagulation), and leading to AOs in various organs

Fig. 2:. Schematic representation of the CIAO network

AOPs developers encompass full participants at one of more working group, CIAO junior collaborators (master or PhD student), consultants offering occasional ad hoc expertise. AOPs users could be scientists, clinicians, epidemiologists among others.

Fig. 3:

The CIAO publication strategy

Fig. 4:. COVID-19 timeline KE and AOPs

(Courtesy of Sally Mayasisch)

Fig. 5:. The Multiscale Health Action Matrix was a collaborative effort by the Multiscale Impact WG to begin to chart the full range of spatiotemporal scales and factors that need to be considered to understand and respond to COVID-19 and future pandemics

The spatial scales (Y-Axis) range from the atomic/ molecular to systems, individuals, society and global-ecological. Temporally (X-Axis), the key events and factors precede the pandemic and personal infection. The timeline extends into the future to include long-COVID and post-pandemic considerations, thus reflecting the cyclical challenge of pandemic conditions.

Fig. 6:

One possible future model of KE structure, where the KE would be grouped as a family or a “node”, e.g., ACE2 dysfunction, and different aspects of the KE would be encoded as sub-categories or “flavors” of the KE