This AOP is licensed under a Creative Commons Attribution 4.0 International License.
SARS-CoV-2 infection leading to hyperinflammation
Point of Contact
- Hasmik Yepiskoposyan
- Arthur Author
|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 Do not cite|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
|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|
AOP Development Strategy
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
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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||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|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
Considerations for Potential Applications of the AOP (optional)
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.