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ACE2 binding to viral S-protein leads to Neuroinflammation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of Sars-CoV-2 spike protein to ACE 2 receptors expressed on brain cells (neuronal and non-neuronal) leads to neuroinflammation resulting in encephalitis||adjacent||High||Low||Agnes Aggy (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Some cytokines released in the blood circulation can cross the BBB and activate the resident brain immune cells like microglia and astrocytes to produce neural cytokines, further worsening the condition (Tjalkens et al. 2017). Astrocytes regulate a wide variety of functions, which may aggravate neuroinflammation. Activated microglia may engulf the neighboring neurons on activation (Mariani et al. 2009; Mahmoud et al. 2019).
Furthermore, microglia are the primary source of pro-inflammatory cytokines, nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species (Mariani et al. 2009). Microglia express ACE-2, along with ACE and AT1 (Cui et al. 2019). These receptors play a significant role in microglia activation and balance the pro-inflammatory or anti-inflammatory effects (Jackson L, et al. 2018) (Murta et al., 2020). More specifically, SARS-CoV-2 infection can hamper the ACE-2-mediated signaling, creating a glitch in the AT1 receptor-mediated path, thereby inducing a pro-inflammatory response (Jackson L, et al. 2018). In vivo studies suggest induction of pro-inflammatory cytokines in microglia and the mouse brain and spinal cord (Li et al. 2004). The situation becomes dreadful when the pro-inflammatory substances produced by astrocytes and microglia fenestrate the BBB (Mariani et al. 2009; Mahmoud et al. 2019).
It was found that the level of neurovirulence of the virus correlates with its differential ability to induce proinflammatory cytokines (interleukin 12 [IL-12] p40, tumor necrosis factor alpha, IL-6, IL-15, and IL-1beta) in astrocytes and microglia and in mouse brains and spinal cords. These findings suggest that coronavirus neurovirulence may depend on a novel discriminatory ability of astrocytes and microglia to induce a proinflammatory response in the CNS (Li et al. 2004).
Evidence Supporting this KER
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Cui C, et al. Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system. Redox Biol. 2019;26:101295.
Jackson L, et al. Within the brain: the renin angiotensin system. Int J Mol Sci. 2018;19.
Li Y, et al. E. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J Virol. 2004;78:3398–3406.
Mahmoud S, et al. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells. 2019 Feb 20;8(2):184.
Mariani MM, Kielian T. Microglia in infectious diseases of the central nervous system. J Neuroimmune Pharmacol. 2009;4:448– 61.
Murta et al. Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders? ASN Neuro. 2020. PMID: 32878468
Tjalkens RB, et al. Inflammatory activation of microglia and astrocytes in manganese neurotoxicity. Adv Neurobiol. 2017;18:159–81.