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

Addressing risk factors in COVID-19 is crucial since abundant clinical evidence shows that COVID-19 outcomes are markedly heterogeneous. This requires both identification of factors modulating the outcomes, but also mechanistic understanding of how they influence COVID-19 pathogenesis. Here, we describe how eleven selected factors influence central COVID-19 mechanisms, by using the Adverse Outcome Pathway (AOP), well-established in regulatory toxicology. This framework aims to model the sequence of events starting from an initial interaction of a stressor (the virus) with the organism at the molecular level through key biological events up to an adverse outcome (a disease). Various linear AOPs depicting the pathway from the binding of the virus to ACE2 up to a clinical outcome observed in COVID-19 patients have been developed and integrated within 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 various factors modulate those events to better understand their impact on the observed differences in clinical outcomes. Applying this novel approach enables the identification of knowledge gaps orientating for further research and allows to capture the interplay between different risk factors. Finally, this AOP-aligned approach facilitates multidisciplinary expertise synergy to address public health issues.

CLERBAUX Laure-Alix;  ALBERTINI Maria Christina;  AMIGO Nuria;  BERONIUS Anna;  BEZEMER Gillina F.G.;  COECKE Sandra;  DASKALOPOULOS Evangelos;  DEL GIUDICE Giusy;  GRECO Dario;  GRENGA Lucia;  MANTOVANI Alberto;  MUNOZ-PINEIRO Maria Amalia;  OMERAGIC Elma;  PARISSIS Nikolaos;  PETRILLO Mauro;  SAARIMAKI Laura A.;  SOARES Helena;  SULLIVAN Kristie;  LANDESMANN Brigitte; 

2022-08-10

MDPI

JRC129180

2077-0383 (online),   

https://www.mdpi.com/2077-0383/11/15/4464,    https://publications.jrc.ec.europa.eu/repository/handle/JRC129180,   

10.3390/jcm11154464 (online),