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Aop: 320

AOP Title

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Binding of viral S-glycoprotein to ACE2 receptor leading to acute respiratory distress associated mortality

Short name:

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S glycoprotein, Acute respiratory distress

Graphical Representation

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Click to download graphical representation template

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Authors

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  • Young Jun Kim  and Yong Oh Lee

         Korea Institute of Science and Technology (KIST) Europe, Saarbrücken 66123, Germany

  • Brigitte Landesmann

          F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM

          Directorate F – Health, Consumers and Reference Materials

          Joint Research Centre, European Commission

  • Penny nymark

         Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden

  • Jukka Sund

          F.3 unit, EURL-ECVAM

          Joint Research Centre, European Commission

 

Point of Contact

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Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim
  • Brigitte Landesmann
  • Penny Nymark

Status

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Author status OECD status OECD project SAAOP status
Open for comment. Do not cite


This AOP was last modified on May 18, 2020 04:55

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Revision dates for related pages

Page Revision Date/Time
Increased, secretion of proinflammatory and profibrotic mediators October 30, 2019 11:28
Enhanced viral entry and gene expression March 01, 2020 10:29
Binding of S protein to ACE receptor March 02, 2020 03:18
Increase, the risk of acute respiratory failure March 10, 2020 02:05
Increase inflammatory immune responses March 10, 2020 02:17
Increased Mortality December 20, 2019 17:34
Binding of S protein to ACE receptor leads to Enhanced viral entry and gene expression March 02, 2020 03:19
Enhanced viral entry and gene expression leads to Increased proinflammatory mediators March 01, 2020 10:31
Increased proinflammatory mediators leads to Increase inflammatory immune responses March 10, 2020 02:18
Increase 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 March 01, 2020 10:42
COVID-19 March 01, 2020 10:46

Abstract

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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 binds 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. 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 report the S glycoprotein of viral capsid in complex with its host cell receptor ACE2 resulted in acute respiratory distress associated 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, and Lung. However, there is an unexplored relationship for ACE2 levels between fibrotic hypersensitivity and Renin-Angiotensin Pathway which caused acute respiratory distress associated mortality.


Background (optional)

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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 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 mortality.


Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
MIE 1739 Binding of S protein to ACE receptor Binding of S protein to ACE receptor
KE 1738 Enhanced viral entry and gene expression Enhanced viral entry and gene expression
KE 1496 Increased, secretion of proinflammatory and profibrotic mediators Increased proinflammatory mediators
KE 1750 Increase inflammatory immune responses Increase 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)

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Title Adjacency Evidence Quantitative Understanding
Binding of S protein to ACE receptor leads to Enhanced viral entry and gene expression adjacent High Low
Enhanced viral entry and gene expression leads to Increased proinflammatory mediators adjacent Low Low
Increased proinflammatory mediators leads to Increase inflammatory immune responses adjacent High Low
Increase 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 High High

Network View

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Stressors

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Name Evidence Term
SARS-CoV High
COVID-19 High

Life Stage Applicability

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Life stage Evidence
Conception to < Fetal High

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI

Sex Applicability

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Sex Evidence
Mixed High

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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This AOP not only contributes new tools to study entry of the viral particles 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.


References

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