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Aop: 406

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

SARS-CoV-2 infection leading to hyperinflammation

Short name

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

SARS-CoV2 to hyperinflammation

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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

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

Arthur Author (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

Hasmik Yepiskoposyan
Arthur Author

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
Under development: Not open for comment. Do not cite

This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page	Revision Date/Time
Binding to ACE2	May 17, 2022 10:20
SARS-CoV-2 cell entry	June 18, 2022 11:10
Increased SARS-CoV-2 production	June 14, 2022 08:49
Diminished protective oxidative stress response	July 03, 2022 22:14
NLRP3 inflammasome activity, increased	June 25, 2021 08:29
Hyperinflammation	December 29, 2021 02:29
Binding to ACE2 leads to SARS-CoV-2 cell entry	October 24, 2022 07:43
SARS-CoV-2 cell entry leads to SARS-CoV-2 production	March 30, 2021 22:06
SARS-CoV-2 production leads to Diminished Protective Response to ROS	April 20, 2021 03:48
Diminished 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

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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

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.

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

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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

KE	1738	SARS-CoV-2 cell entry	SARS-CoV-2 cell entry
KE	1847	Increased SARS-CoV-2 production	SARS-CoV-2 production
KE	1869	Diminished protective oxidative stress response	Diminished Protective Response to ROS
KE	1895	NLRP3 inflammasome activity, increased	inflammasome activity, increased

1868

Hyperinflammation

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

Title	Adjacency	Evidence	Quantitative Understanding

Binding to ACE2 leads to SARS-CoV-2 cell entry	adjacent
SARS-CoV-2 cell entry leads to SARS-CoV-2 production	adjacent
SARS-CoV-2 production leads to Diminished Protective Response to ROS	adjacent
Diminished Protective Response to ROS leads to inflammasome activity, increased	adjacent
inflammasome activity, increased leads to Hyperinflammation	adjacent

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

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

Sex Applicability

The sex for which the AOP is known to be applicable. More help

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

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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

References

List of the literature that was cited for this 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.