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Relationship: 2358

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

SARS-CoV-2 production leads to Diminished Protective Response to ROS

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

SARS-CoV-2 production

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Diminished Protective Response to ROS

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation	adjacent	Moderate	Not Specified	Arthur Author (send email)	Under development: Not open for comment. Do not cite	Under Development
SARS-CoV-2 infection leading to hyperinflammation	adjacent			Arthur Author (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

ROS is generated upon the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in coronavirus disease 2019 (COVID-19), and induces oxidative stress (Janardhan VV and Kalousek V, 2020). SARS-CoV-2 infection induces cytokine storm (Frisoni P et al., 2021, Kaidashev I et al., 2021). Cytokine storm includes ROS-induced oxidative stress and immune cell dysregulation. Glutathione S-transferase genes, which have functions in the elimination of ROS, involves the morbidity and mortality from COVID-19 (Kaidashev I et al., 2021). The heme oxygenase-1 (HO-1) induction may be involved in the inflammation-induced coagulation in COVID-19 (Kaidashev I et al., 2021). ROS quenching by vitamin C, E, beta-carotene and polyphenols has been suggested in COVID-19 in the point of view of the nutrient, since oxidative stress causes inflammation (Iddir M et al., 2020). Potential roles of omega-3 fatty acids accompanied by antioxidants have been suggested in the cytokine storm due to SARS-CoV-2 infection (Rogero MM, 2020).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

References were selected based on the knowledge. The evidence was collected with literature search with key words including "reactive oxygen species" and "SARS-CoV-2" and NRF2. Some of the content of the literature has been summarized in Editorial (Tanabe S, 2021).

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Increased coronavirus production increase in angiotensin II (Ang II). Ang II increases ROS production via NADPH oxidase activation (Nishida et al., 2005). Coronavirus pathogenesis pathway is involved in molecules in production of reactive oxygen species (ROS), oxidative stress responses (Tanabe, 2021). The fixation of SARS-CoV-2 in angiotensin-converting enzyme 2 (ACE2) receptor results in reduction of AC2 activity, leading to dysfunction of the renin-angiotensin system (RAS) and excessive production of pro-inflammatory and pro-oxidant agents (Ramdani and Bachari, 2022).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Nrf2 activator, dimethyl fumarate(DMF), which was recently approved for the treatment of multiple sclerosis, and is a potent anti-oxidant and anti-inflammatory agent inhibiting the NF-kappaB pathway through binding and activation of the IKKbeta at Cys-179, inhibited SARS-CoV-2 entry (Hassan et al., 2020). As SARS-CoV-2 is attached to ACE2, ACE2 is not available within the renin-angiotensin system to convert Ang II to angiotensin-(1,7) resulting in Ang II to accumulate. Ang II stimulates membrane-bound NADPH oxidase, which in turn generate ROS and oxidative stress (Janardhan et al., 2020). Resveratrol, a natural compound possessing anti-oxidant properties by trapping ROS, has a potential to inhibit SARS-CoV-2 infection (Ramdani and Bachari, 2020, van Brummelen and van Brummelen, 2022).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The transient up-regulation of ROS may serve as an inhibitory factor of pathogen (Zhu et al., 2021).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Selenium	Nutrient	Lower level of selenium and higher levels of reactive oxygen species are observed in COVID-19 patients.	Šķesters et al. 2023
Vitamin D	Nutrient	Vitamin D supplementation reduce the number of virus particles that could attach to ACE2 and enter the cell.	Iddir M et al. 2020

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Quercetin inhibits one of the main proteases highly conserved among coronaviruses, SARS-CoV-2 3CLpro (Ki = ~7 uM) (Abian, Ortega-Alarcon et al. 2020).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Angiotensin II dose-dependently increases ROS (Nishida, Tanabe et al. 2005).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Catalytic activity of SARS-CoV-2 3CLpro or inhibitory effect of the SARS-CoV-2 3CLpro can be measured in 10-100 sec or 10-40 min in vitro (Abian, Ortega-Alarcon et al. 2020).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The KER applies to species including Homo sapiens which have ACE2 receptors to bind to SARS-CoV-2 and protective responsive system to ROS, as ROS scavenging system. The KER has relatively broad applicability among Homo sapiens.

References

List of the literature that was cited for this KER description. More help

Abian, O., D. Ortega-Alarcon, A. Jimenez-Alesanco, L. Ceballos-Laita, S. Vega, H. T. Reyburn, B. Rizzuti and A. Velazquez-Campoy (2020). "Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening." International Journal of Biological Macromolecules 164: 1693-1703.

Frisoni P, Neri M, D’Errico S, Alfieri L, Bonuccelli D, et al. (2021) Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1β, IL-6, IL-15 and TNF-α. Forensic Sci Med Pathol. 31:1-15.

Hassan, S. M., M. J. Jawad, S. W. Ahjel, R. B. Singh, J. Singh, S. M. Awad and N. R. Hadi (2020). "The Nrf2 Activator (DMF) and Covid-19: Is there a Possible Role?" Med Arch 74(2): 134-138.

Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, et al. (2020) Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 12(6):1562.

Janardhan, V., V. Janardhan and V. Kalousek (2020). "COVID-19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy." Journal of Neuroimaging 30(5): 555-561.

Kaidashev I, Shlykova O, Izmailova O, Torubara O, Yushchenko Ya, et al. (2021) Host gene variability and SARS-CoV-2 infection: A review article. Heliyon. 7(8): e07863.

Nishida, M., S. Tanabe, Y. Maruyama, S. Mangmool, K. Urayama, Y. Nagamatsu, S. Takagahara, J. H. Turner, T. Kozasa, H. Kobayashi, Y. Sato, T. Kawanishi, R. Inoue, T. Nagao and H. Kurose (2005). "G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes." J Biol Chem 280(18): 18434-18441.

Ramdani, L.H., K. Bachari. (2020). "Potential therapeutic effects of Resveratrol against SARS-CoV-2 " Acta virologica 64.

Rogero MM. (2020) Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19. Free Radic Biol Med. 156:190-99.

Šķesters A, Lece A, Kustovs D, Zolovs M. Selenium Status and Oxidative Stress in SARS-CoV-2 Patients. Medicina (Kaunas). 2023 Mar 8;59(3):527. doi: 10.3390/medicina59030527.

Tanabe S. (2021) Involvement of Reactive Oxygen Species (ROS) and Coagulation in Coronaviral Infection. Adv Clin Med Res. 2(2):21.

van Brummelen, R. and A. C. van Brummelen (2022). "The potential role of resveratrol as supportive antiviral in treating conditions such as COVID-19 – A formulator’s perspective." Biomedicine & Pharmacotherapy 148: 112767.

Zhu, Z., Z. Zheng and J. Liu (2021). "Comparison of COVID-19 and Lung Cancer via Reactive Oxygen Species Signaling." Front Oncol 11: 708263.