The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19
Helena T. Hogberg,
Ann Lam,
Elan Ohayon,
Muhammad Ali Shahbaz,
Laure-Alix Clerbaux,
Anna Bal-Price,
Sandra Coecke,
Rachel Concha,
Francesca De Bernardi,
Eizleayne Edrosa,
Alan J. Hargreaves,
Katja M. Kanninen,
Amalia Munoz,
Francesca Pistollato,
Surat Saravanan,
Natàlia Garcia-Reyero,
Clemens Wittwehr,
Magdalini Sachana
Affiliations
Helena T. Hogberg
National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27518, USA
Ann Lam
Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA
Elan Ohayon
Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA
Muhammad Ali Shahbaz
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Laure-Alix Clerbaux
European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
Anna Bal-Price
European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
Sandra Coecke
European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
Rachel Concha
Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA
Francesca De Bernardi
Division of Otorhinolaryngology, Department of Biotechnologies and Life Sciences, University of Insubria, Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy
Eizleayne Edrosa
Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA
Alan J. Hargreaves
School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
Katja M. Kanninen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Amalia Munoz
European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium
Francesca Pistollato
European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
Surat Saravanan
Centre for Predictive Human Model Systems Atal Incubation Centre-Centre for Cellular and Molecular Biology, Hyderabad 500039, India
Natàlia Garcia-Reyero
Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS 39180, USA
Clemens Wittwehr
European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
Magdalini Sachana
Environment Health and Safety Division, Environment Directorate, Organisation for Economic Cooperation and Development (OECD), 75016 Paris, France
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.
