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AOP: 374


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

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

Short name
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Sars-CoV-2 causes encephalitis
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

Graphical Representation

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European Commission, Join Research Centre (JRC), Ispra, Italy

Point of Contact

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Agnes Aggy   (email point of contact)


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  • Anna Price
  • Francesca Pistollato
  • Agnes Aggy


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  • Cinzia La Rocca

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.96 Under Development
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Binding to ACE2 August 30, 2023 20:36
Neuroinflammation July 15, 2022 09:54
N/A, Neurodegeneration February 23, 2021 05:07
Encephalitis February 23, 2021 05:22
Binding to ACE2 leads to Neuroinflammation February 23, 2021 05:33
Neuroinflammation leads to N/A, Neurodegeneration February 23, 2021 05:47
N/A, Neurodegeneration leads to Encephalitis February 23, 2021 06:04
Neuroinflammation leads to Encephalitis February 23, 2021 06:17
Sars-CoV-2 September 09, 2022 05:09
Virus May 29, 2018 07:10
bacteria February 23, 2021 05:15


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Although the severe acute respiratory syndrome COVID-19 caused by the virus SARS-CoV-2 mainly manifests as an effect of acute respiratory infection (Radnis et al. 2020), recent evidence also suggests that approximately 36% of affected patients exhibit neurological sequelae (Mao et al., 2020).

Many studies have shown that SARS-CoV-2 coronavirus is neuroinvasive, neurotropic, and neurovirulent in humans. The presence of SARS-CoV-2 has been identified in the central nervous system (CNS) and cerebrospinal fluid (CSF) of patients with acute neurologic symptoms, including encephalitis (Wu et al., 2020).  Post-mortem examination of SARS-CoV-2-infected patients revealed the presence of SARS-CoV-2 viral particles in endothelial cells and pericytes of brain capillaries and neurons (Paniz-Mondolfi et al., 2020; Nath, 2020; Chigr et al. 2020) as well as in glial cells (microglia and astrocytes) (Vargas et al. 2020; Nakagaki et al., 2005; Lannes et al., 2017).

There are several routes of Sars-CoV-2 entry into the CNS. The presence of viral-like particles of SARS-CoV-2 in endothelial cells and pericytes of brain capillaries, as well as astrocytic processes, strongly supports a hematogenous endothelial neuroinvasion-based hypothesis (Paniz-Mondolfi et al., 2020). Indeed, SARS-CoV-2 induced over-activation of systemic immune cells and the release of pro-inflammatory chemokines and cytokines, provokes a cytokine storm possibly leading to the to disruption of the tight junctions and increased permeability of the blood brain barrier (BBB) (Savarin and Bergmann 2018).

In parallel, SARS-CoV-2 could also infect the endothelial cells of the blood-cerebrospinal fluid barrier, and then spread into the CNS. Olfactory pathway (through nasal epithelium), vagus and trigeminal nerves, as well as the enteric nervous system are other possible routes of probable Sars-CoV-2 entry into the CNS.

Binding of S protein to ACE2 receptors on microglia triggers their activation, which results in the release of proinflamatory cytokines/chemokines, nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. As a consequence, activation of astrocytes occurs, which ultimately may lead to neuronal cell death (Ransohoff and Perry, 2009; Chatterjee et al., 2013; Wheeler et al., 2018). This proinflamatory factors can trigger neuronal cell death by well-known mechanisms contributing, together with brain neuroinflammation, to encephalitis.

Encephalitis has been documented in clinical observations in COVID-19 patients, characterized by acute onset and common symptoms include headache, fever, vomiting, convulsions, and consciousness disorders (Wu Y et al., 2020).  In the ongoing pneumonia epidemic, the presence of Sars-CoV-2 in the CSF of patients with COVID-19 was confirmed by genome sequencing, thereby clinically verifying viral encephalitis (Xiang et al., 2020), providing a solid basis for Sars-CoV-2 as a cause of this disease.

The present AOP describes current mechanistic understanding of causative links between binding of Spike protein to ACE2 receptors on brain cells, which leads to glia activation, neuronal inflammation and cell death, resulting in encephalitis (adverse outcome), which manifests through a variety of symptoms including headache, high fever, vomiting, convulsions, and consciousness disorders, as observed in several clinical studies in COVID-19 patients.

AOP Development Strategy


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

Two KEs of this AOP (i.e., neuroinflammation and neurodegeneration) have been described in other AOPs (i.e., neuroinflammation (in AOP 12, AOP 48, AOP 3, and AOP 17); neurodegeneration (in AOP 12, AOP 48, AOP 281); however, quantitative information of KERs is limited or non-existing.


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Summary of the AOP

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Molecular Initiating Events (MIE)
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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 Binding to ACE2
KE 188 Neuroinflammation Neuroinflammation
KE 352 N/A, Neurodegeneration N/A, Neurodegeneration
AO 1841 Encephalitis Encephalitis

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding

Network View

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Prototypical Stressors

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Life Stage Applicability

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Life stage Evidence
Adults High

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

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Sex Evidence
Mixed High

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

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Essentiality for MIE:

SARS-CoV-2 was able to infect and kill neural cells, including cortical neurons. This phenotype was accompanied by impaired synaptogenesis. Sofosbuvir, an FDA-approved antiviral drug, was able to rescue these alterations (Mesci et al, 2020). It is speculated that the viral mediated production of autoantibodies against glial cells might be responsible for neural injury (Zanin et al., 2020). Neural infection can be prevented by using either anti-ACE2 antibodies or anti-spike antibodies from the cerebrospinal fluid (CSF) of COVID-19 patients (Mesci et al., 2020). Organoids incubated with either anti-ACE2 antibodies or anti-spike antibodies from the CSF of COVID-19 patients saw a significant decrease in SARS-CoV-2 infection. Likewise, transgenic mice overexpressing human ACE2 were used to demonstrate viral replication in the brain and the lethal consequences of SARS-CoV-2 CNS infection. SARS-CoV-2 infected mice overexpressing human ACE2 showed increase viral titers in the brain and death associated to neuroinvasion (Song et al., 2020).

Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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

AOP 12 Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging. Available at

AOP 17 Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory. Available at

AOP 281 Acetylcholinesterase Inhibition Leading to Neurodegeneration. Available at

AOP 3 Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits. Available at

AOP 48 Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment. Available at

Chatterjee D, et al. Microglia play a major role in direct viral-induced demyelination. Clin Dev Immunol. 2013; 2013():510396.

Chigr F., et al. Comment on “The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients”. J Med Virol. 2020 Jul;92(7):703-704.

Lannes N., Neuhaus V., Scolari B., Kharoubi-Hess S., Walch M., Summerfield A., Filgueira L. Interactions of human microglia cells with Japanese encephalitis virus. Virol. J. 2017;14(1):8.

Mao et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology (2020) 77(6): 683–690.

Mesci P et al. Sofosbuvir protects human brain organoids against SARS-CoV-2. bioRxiv. 2020. Available at: doi:

Nakagaki K., Nakagaki K., Taguchi F. Receptor-independent spread of a highly neurotropic murine coronavirus JHMV strain from initially infected microglial cells in mixed neural cultures. J. Virol. 2005;79(10):6102–6110.

Nath A, Smith B. Neurological issues during COVID-19: An overview. Neurosci Lett. 2021 Jan 18;742:135533.

Paniz-Mondolfi et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Med Virol. 2020 Jul;92(7):699-702.

Radnis C, et al. Radiographic and clinical neurologic manifestations of COVID-19 related hypoxemia. J Neurol Sci. 2020 Nov 15;418:117119. Gallagher et al., 2006;

Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009; 27():119-45.

Savarin C, Bergmann CC. Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis. Front Immunol. 2018 Dec 20;9:3022.

Song et al. Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model. bioRxiv. 2020. Available at:

Vargas G. et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives. Brain Behav Immun Health. 2020 Aug; 7: 100127.

Wheeler DL, et al. Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest. 2018 Mar 1; 128(3):931-943.

Wu Y, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020 Jul;87:18-22.

Xiang YT, et al. The COVID-19 outbreak and psychiatric hospitals in China: managing challenges through mental health service reform. Int J Biol Sci. 2020 Mar 15;16(10):1741-1744.

Zanin L, et al. SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir (Wien). 2020 Jul;162(7):1491-1494.