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SARS-CoV-2 production leads to Diminished Protective Response to ROS
Key Event Relationship Overview
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||Shihori Tanabe (send email)||Under development: Not open for comment. Do not cite||Under Development|
|SARS-CoV-2 infection leading to hyperinflammation||adjacent||Hasmik Yepiskoposyan (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
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
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
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).
Uncertainties and Inconsistencies
The transient up-regulation of ROS may serve as an inhibitory factor of pathogen (Zhu et al., 2021).
Known modulating factors
|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|
Angiotensin II dose-dependently increases ROS (Nishida, Tanabe et al. 2005).
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
Domain of Applicability
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.
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.