Aop: 320

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Binding of SARS-CoV-2 to ACE2 receptor leading to acute respiratory distress associated mortality

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
SARS-CoV-2 leads to acute respiratory distress

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Young Jun Kim1, Yongoh Lee1, Jihun Yang2, Chung Seok2,3 Brigitte Landesmann4, Laure-Alix Clerbaux4 , Penny Nymark5, Jukka Sund6, Filipovska, Julija7, Shihori Tanabe8, Gillian Bezemer9, Maria Joao Amorim10 and HyunJoon Kong11 

1Korea Institute of Science and Technology (KIST) Europe, Saarbrücken 66123, Germany, 2 NEXT&BIO, South Korea,  3KU-KIST Graduate School of Converging Science and Technology, South Korea 4 F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM, Directorate F – Health, Consumers and Reference Materials Joint Research Centre, European Commission  5 Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden 6 F.3 unit, EURL-ECVAM Joint Research Centre, European Commission Independent,  North Macedonia  8 Division of Risk Assessment, Center for Biological Safety and Research National Institute of Health Sciences, Japan 9 Impact Station, Universiteit Utrecht, Nederland 10 Instituto Gulbenkian de Ciência, Portugal 11 University of Illinois at Urbana-Champaign, USA

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Young Jun Kim   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Young Jun Kim
  • Brigitte Landesmann
  • Penny Nymark
  • Shihori Tanabe
  • Gillina Bezemer
  • Julija Filipovska
  • Hyunjoon Kong
  • Maria Joao Amorim
  • Laure-Alix Clerbaux

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
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

Revision dates for related pages

Page Revision Date/Time
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

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

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.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Conception to < Fetal High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

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.

References

List of the literature that was cited for this AOP. More help
  1.  Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM (Aug 2005). "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury". Nature Medicine. 11 (8): 875–9. doi:10.1038/nm1267PMID 16007097.
  2. "What are the official names of the disease and the virus that causes it?". Q&A on coronaviruses. World Health Organization. Retrieved 22 February 2020.
  3. Zhou P, Yang X (2020-02-03). "A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin". Nature. doi:10.1038/s41586-020-2012-7PMID 32015507.
  4. Xintian, Xu; Chen, Ping (2020). "Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission". Science China Life Sciences. doi:10.1007/s11427-020-1637-5PMID 32009228.
  5. Understanding COVID-19 through adverse outcome pathways – 2nd CIAO AOP Design Workshop doi.org/10.14573/altex.2102221
  6.  Lewis, Ricki. "COVID-19 Vaccine Will Close in on the Spikes". DNA Science Blog. Public Library of Science. Retrieved 22 February 2020.
  7.  Walls, Alexandra; et al. (2020). "Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein". bioRxiv. bioRxiv. doi:10.1101/2020.02.19.956581. Retrieved 22 February 2020.
  8. He L,et al (2006).Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.J Pathol. 2006 Nov;210(3):288-97.​
  9. Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett , Jory A. Goldsmith, Ching-Lin Hsieh , Olubukola Abiona , Barney S. Graham , Jason S. McLellan Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Wrapp et al., Science 367, 1260–1263 (2020)
  10. Hamming ITimens WBulthuis MLLely ATNavis Gvan Goor H Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J Pathol. 2004 Jun;203(2):631-7
  11. Xie Xudong et al.Age- and gender-related difference of ACE2 expression in rat lung Life Sciences Volume 78, Issue 19, 4 April 2006, Pages 2166-2171
  12. Kim Y et al. Advanced Adverse Outcome Pathways Potentially Bridging the Pathogenesis of COVID-19, 2021,  doi: 10.20944/preprints202101.0065.v1 
  13. Penny Nymark et al. Systematic Organization of COVID-19 Data Supported by the Adverse Outcome Pathway Framework, 2021,doi: 10.20944/preprints202101.0573.v1
  14. Mathieu Vinke,  A putative AOP for pneumonia related to COVID-19, 2020, Archives of Toxicology 94(9)