This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Binding of SARS-CoV-2 to ACE2 receptor leading to acute respiratory distress associated mortality
Point of Contact
- Young Jun Kim
- Brigitte Landesmann
- Penny Nymark
- Shihori Tanabe
- Gillina Bezemer
- Julija Filipovska
- Hyunjoon Kong
- Maria Joao Amorim
- Laure-Alix Clerbaux
|Author status||OECD status||OECD project||SAAOP status|
|Open for comment. Do not cite||Under Development||1.96||Included in OECD Work Plan|
This AOP was last modified on June 16, 2022 10:37
|Increased, secretion of proinflammatory mediators||January 25, 2022 15:50|
|SARS-CoV-2 cell entry||July 21, 2022 11:14|
|Binding to ACE2||May 17, 2022 10:20|
|Increase, the risk of acute respiratory failure||March 10, 2020 02:05|
|Increased inflammatory immune responses||January 21, 2021 03:35|
|Increased Mortality||July 08, 2022 07:32|
|Toll Like Receptor (TLR) Dysregulation||November 23, 2021 16:54|
|Increased SARS-CoV-2 production||June 14, 2022 08:49|
|Interferon-I antiviral response, antagonized by SARS-CoV-2||June 14, 2022 10:29|
|Binding to ACE2 leads to SARS-CoV-2 cell entry||July 21, 2022 07:03|
|SARS-CoV-2 production leads to TLR Activation/Dysregulation||April 16, 2021 04:29|
|TLR Activation/Dysregulation leads to Increased proinflammatory mediators||March 29, 2021 06:48|
|Increased proinflammatory mediators leads to Increased inflammatory immune responses||March 10, 2020 02:18|
|Increased inflammatory immune responses leads to Increase, the risk of acute respiratory failure||March 10, 2020 02:19|
|Increase, the risk of acute respiratory failure leads to Increased Mortality||May 13, 2020 09:39|
|SARS-CoV-2 cell entry leads to IFN-I response, antagonized||May 31, 2022 18:07|
|IFN-I response, antagonized leads to SARS-CoV-2 production||October 24, 2021 17:11|
|SARS-CoV||March 01, 2020 10:42|
|HCoV-NL63||February 07, 2021 07:01|
|Sars-CoV-2||February 23, 2021 04:50|
Inhalation of substances, including viral particles, the RNA virus capsid (S) glycoprotein binds the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediates fusion of the viral and cellular membranes through a pre- to postfusion conformation transition. The S protein is cleaved into S1 and S2 units by a human cell-derived protease (proteolytic enzyme) that is assumed to be Furin.S1 units then bind to its receptor, ACE2. The other fragment, S2, is cleaved by TMPRSS2, a human cell surface serine protease, resulting in cell membrane fusion. The S protein binds the catalytic domain of ACE2 with high affinities likewise, COVID-19 shares 79.6% homology of SARS-CoV and 96% identical at the whole-genome level to a bat coronavirus. The binding of the coronavirus S protein to ACE2 triggers a conformational change in the S protein of the coronavirus, allowing for proteolytic digestion by host cell proteases called TMPRSS2. The AOP reports the S glycoprotein of viral capsid in complex with its host cell receptor ACE2 resulted in acute respiratory distress associated with mortality by cytokine storms and enhanced inflammation in pulmonary tissue. S-glycoprotein of the virus uses ACE2 to get into cells that are found on the surface of epithelial cells in Kidney, Heart, Liver and Lung. However, there is an unexplored relationship for ACE2 levels between fibrotic hypersensitivity and Renin-Angiotensin Pathway which caused acute respiratory distress associated with mortality.
AOP Development Strategy
The ACE2 gene encodes the angiotensin-converting enzyme-2, which has been proved to be the receptor for both the SARS-coronavirus (SARS-CoV) and the human respiratory coronavirus. ACE2 is a key component of blood pressure regulation in the renin-angiotensin system. Angiotensin (Ang) converting enzyme 2 (ACE2) is a homolog of ACE. ACE2 negatively regulates the renin-angiotensin system (RAS) by converting Ang II to Ang-(1-7) and AngI to Ang(1-9). The higher levels of receptor expression achieved by the expression of recombinant ACE2 could be relevant for cell-cell fusion. The underlying mechanisms remain to be elucidated and could play a role in the entry of the cell-free virus into cells and finally increase the acute respiratory distress associated with mortality.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||1739||Binding to ACE2||Binding to ACE2|
|KE||1738||SARS-CoV-2 cell entry||SARS-CoV-2 cell entry|
|KE||1901||Interferon-I antiviral response, antagonized by SARS-CoV-2||IFN-I response, antagonized|
|KE||1847||Increased SARS-CoV-2 production||SARS-CoV-2 production|
|KE||1848||Toll Like Receptor (TLR) Dysregulation||TLR Activation/Dysregulation|
|KE||1496||Increased, secretion of proinflammatory mediators||Increased proinflammatory mediators|
|KE||1750||Increased inflammatory immune responses||Increased inflammatory immune responses|
|KE||1748||Increase, the risk of acute respiratory failure||Increase, the risk of acute respiratory failure|
|AO||351||Increased Mortality||Increased Mortality|
Relationships Between Two Key Events (Including MIEs and AOs)
|Binding to ACE2 leads to SARS-CoV-2 cell entry||adjacent||High||High|
|SARS-CoV-2 production leads to TLR Activation/Dysregulation||adjacent||Moderate||Not Specified|
|TLR Activation/Dysregulation leads to Increased proinflammatory mediators||adjacent||High||Not Specified|
|Increased proinflammatory mediators leads to Increased inflammatory immune responses||adjacent||High||Low|
|Increased inflammatory immune responses leads to Increase, the risk of acute respiratory failure||adjacent||Moderate||Low|
|Increase, the risk of acute respiratory failure leads to Increased Mortality||adjacent||Moderate||Not Specified|
|SARS-CoV-2 cell entry leads to IFN-I response, antagonized||adjacent||High|
|IFN-I response, antagonized leads to SARS-CoV-2 production||adjacent||High|
Life Stage Applicability
|Conception to < Fetal||High|
|Homo sapiens||Homo sapiens||Moderate||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
Considerations for Potential Applications of the AOP (optional)
This AOP not only contributes new tools to study entry of the viral particles or Inhalation of stressors into cells and localize its receptor-binding domain of ACE2 but also could serve in the development of novel vaccine immunogens against TMPRSS2 proteases which may inhibit cell entry of COVID-19.
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