The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19

Abstract

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood-brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.

Keywords: AOP; SARS-CoV-2; anosmia; encephalitis; human-specific research; neuropathology; stroke.

Figure 1

Integration of classical AOPs. Neuronal-related AOPs developed so far within the CIAO dedicated neuro working group integrated into an AOP network. Some of these AOPs are already uploaded on the AOP-Wiki, whereas others are only drafted outside the platform. The AOP network was built on 18 KEs, including 4 MIEs, 8 specialized (neuro-related) Kes, and 4 AOs. Two of these KEs were already available in the AOP-Wiki while the others were developed within the CIAO project. The dotted lines indicate not fully developed AOPs.

Figure 2

Disparities and sub-pathways to neuro and pulmonary outcomes. The figure illustrates how disparities may instigate psychological stress, leading to both neuroinflammatory and pulmonary inflammation. Pulmonary events can, in turn, lead to hypoxia and additional neurological events. The figure serves as an example of how a multiscale pathway perspective might be presented while concurrently developing the graphical and computational tools that will allow for the representation and analysis of these events and factors across scales.