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Aop: 406

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

SARS-CoV-2 infection leading to hyperinflammation

Short name

A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

SARS-CoV2 to hyperinflammation

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.' Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you. Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Click to download graphical representation template

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate. More help

Arthur Author (email point of contact)

Contributors

List user names of all authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact. More help

Hasmik Yepiskoposyan
Arthur Author

Status

The status section is used to provide AOP-KB 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. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help

Author status	OECD status	OECD project	SAAOP status
Under development: Not open for comment. Do not cite

This AOP was last modified on May 08, 2022 11:33

The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page	Revision Date/Time
ACE2 binding to viral S-protein	November 24, 2021 05:41
Increased susceptibility to viral entry	April 27, 2021 19:46
Increased coronavirus production	April 20, 2021 00:54
Depletion of protective oxidative stress response	January 05, 2022 00:04
NLRP3 inflammasome activity, increased	June 25, 2021 08:29
Hyperinflammation	December 29, 2021 02:29
ACE2 binding to viral S-protein leads to Increased susceptibility to viral entry	March 02, 2020 03:19
Increased susceptibility to viral entry leads to Increased SARS-CoV-2 production	March 30, 2021 22:06
Increased SARS-CoV-2 production leads to Depleted Protective Response to ROS	April 20, 2021 03:48
Depleted Protective Response to ROS leads to inflammasome activity, increased	June 25, 2021 05:24
inflammasome activity, increased leads to Hyperinflammation	June 25, 2021 05:24

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Background (optional)

This optional subsection should be 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Attempts to understand molecular mechanisms of COVID-10 pathogenesis lead to several studies linking COVID-19 severity to oxidative stress in infected tissues (Bakadia, Boni et al. 2021, Mehri, Rahbar et al. 2021, Pincemail, Cavalier et al. 2021). In parallel, the antioxidant defensive mechanisms were lowered in COVID-19 patients (Pincemail, Cavalier et al. 2021). Reactive oxygen species (ROS) and oxidative stress are known to activate inflammasomes (Cruz, Rinna et al. 2007, Martinon 2010, Kauppinen, Niskanen et al. 2012, Abderrazak, Syrovets et al. 2015). Inflammasomes are critical components of innate immune system that induce secretion of pro-inflammatory cytokines such as IL1B and IL18 upon activation (Martinon, Burns et al. 2002, Kelley, Jeltema et al. 2019). In the study by Lage and colleagues, aberrant levels of oxidative stress hallmarks (such as mitochondrial superoxide and lipid peroxidation) with concomitant NLRP3 inflammasome activation and IL1B secretion were observed in monocytes of COVID-19 patients (Lage, Amaral et al. 2021). Since the outbreak of pandemics, several review articles postulated the involvement of oxidative stress and inflammasome activation in COVID-19 pathology (Beltrán-García, Osca-Verdegal et al. 2020, Derouiche 2020, Shah 2020) however the causality of ROS in the inflammasome activation in the context of COVID-19 infection is not very clear.

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 stressor and the biological system) of an AOP. More help

Key Events (KE)

This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page. More help

Adverse Outcomes (AO)

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Sequence	Type	Event ID	Title	Short name

MIE

1739

ACE2 binding to viral S-protein

2	KE	1738	Increased susceptibility to viral entry	Increased susceptibility to viral entry
3	KE	1847	Increased coronavirus production	Increased SARS-CoV-2 production
4	KE	1869	Depletion of protective oxidative stress response	Depleted Protective Response to ROS
5	KE	1895	NLRP3 inflammasome activity, increased	inflammasome activity, increased

1868

Hyperinflammation

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button. Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.). Click ‘Create [adjacent/non-adjacent] relationship.’ The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Title	Adjacency	Evidence	Quantitative Understanding

ACE2 binding to viral S-protein leads to Increased susceptibility to viral entry	adjacent
Increased susceptibility to viral entry leads to Increased SARS-CoV-2 production	adjacent
Increased SARS-CoV-2 production leads to Depleted Protective Response to ROS	adjacent
Depleted Protective Response to ROS leads to inflammasome activity, increased	adjacent
inflammasome activity, increased leads to Hyperinflammation	adjacent

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and 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

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help

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 in relation to this KE. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications. More help

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together. Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook. More help

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections. The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Abderrazak, A., T. Syrovets, D. Couchie, K. El Hadri, B. Friguet, T. Simmet and M. Rouis (2015). "NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases." Redox Biol 4: 296-307.

Bakadia, B. M., B. O. O. Boni, A. A. Q. Ahmed and G. Yang (2021). "The impact of oxidative stress damage induced by the environmental stressors on COVID-19." Life Sci 264: 118653.

Beltrán-García, J., R. Osca-Verdegal, F. V. Pallardó, J. Ferreres, M. Rodríguez, S. Mulet, F. Sanchis-Gomar, N. Carbonell and J. L. García-Giménez (2020). "Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression." Antioxidants (Basel) 9(10).

Cruz, C. M., A. Rinna, H. J. Forman, A. L. Ventura, P. M. Persechini and D. M. Ojcius (2007). "ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages." J Biol Chem 282(5): 2871-2879.

Derouiche, S. (2020). "Oxidative Stress Associated with SARS-Cov-2 (COVID-19) Increases the Severity of the Lung Disease - A Systematic Review." Journal of Infectious Diseases and Epidemiology.

Kauppinen, A., H. Niskanen, T. Suuronen, K. Kinnunen, A. Salminen and K. Kaarniranta (2012). "Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells--implications for age-related macular degeneration (AMD)." Immunol Lett 147(1-2): 29-33.

Kelley, N., D. Jeltema, Y. Duan and Y. He (2019). "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation." Int J Mol Sci 20(13).

Lage, S. L., E. P. Amaral, K. L. Hilligan, E. Laidlaw, A. Rupert, S. Namasivayan, J. Rocco, F. Galindo, A. Kellogg, P. Kumar, R. Poon, G. W. Wortmann, J. P. Shannon, H. D. Hickman, A. Lisco, M. Manion, A. Sher and I. Sereti (2021). "Persistent Oxidative Stress and Inflammasome Activation in CD14(high)CD16(-) Monocytes From COVID-19 Patients." Front Immunol 12: 799558.

Martinon, F. (2010). "Signaling by ROS drives inflammasome activation." Eur J Immunol 40(3): 616-619.

Martinon, F., K. Burns and J. Tschopp (2002). "The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta." Mol Cell 10(2): 417-426.

Mehri, F., A. H. Rahbar, E. T. Ghane, B. Souri and M. Esfahani (2021). "Changes in oxidative markers in COVID-19 patients." Arch Med Res 52(8): 843-849.

Pincemail, J., E. Cavalier, C. Charlier, J. P. Cheramy-Bien, E. Brevers, A. Courtois, M. Fadeur, S. Meziane, C. L. Goff, B. Misset, A. Albert, J. O. Defraigne and A. F. Rousseau (2021). "Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study." Antioxidants (Basel) 10(2).

Shah, A. (2020). "Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19." Front Immunol 11: 1021.