You are here:
Early Key Events for CIAO COVID-19 AOP Design
Citation:
Mayasich, S. AND C. LaLone. Early Key Events for CIAO COVID-19 AOP Design. Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP) Framework (CIAO), Duluth, MN, March 25, 2021. https://doi.org/10.23645/epacomptox.14312486
Impact/Purpose:
The Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP) Framework (CIAO) working group seeks to use the AOP framework to better understand and organize the information needed to treat COVID-19, support new research to defeat the disease, and prevent future pandemics. Early Key Events (KEs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection involve evading the host’s innate immune response and hijacking host molecular machinery to allow for viral replication and transmission. This slide proposes the importance of these early KEs in disease transmission, both human-to-human and across species through alternate hosts. This is a lead-in for future cross-species transmission investigation featuring a novel application of the US EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool, that compares species similarity or differences at the protein level, toward identifying which species may be intermediate hosts.
Description:
Viral protein interactions with host proteins in humans and other organisms are important for the transmission of SARS-CoV2. Understanding each step of the process by which host proteins interact with the viral proteins in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) would help in identifying therapeutics for treatment in humans, preventing of human-to-human transmission, as well as identifying which species may have the appropriate molecular machinery for cross-species transmission of the virus. Cell entry, which is the molecular initiating event (MIE), is immediately followed by KE1, antagonism of the Interferon-I antiviral response. Translation of ORF1ab as the first step in this immune evasion process, then the viral proteins block host proteins in the IFN-I signaling cascade. In KE2, viral replication to increase viral load, replication of the viral genome and transcription and translation of the viral sub-genome occur, within which numerous protein-protein interactions between SARS-CoV-2 and human proteins could be targeted by therapeutics. Additionally, these target proteins remain unexplored as to which species are likely to have similar viral interactions to those in humans. This pathway could also be seen as its own AOP resulting in human or cross-species transmission as the Adverse Outcome, considering the fact that there may be no further disease pathology in some hosts.
