Aop: 374

Title

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
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Sars-CoV-2 causes encephalitis

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Agnes Aggy   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Anna Price
  • Francesca Pistollato
  • Agnes Aggy

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.96 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Binding to ACE2 May 17, 2022 10:20
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 February 23, 2021 04:50
Virus May 29, 2018 07:10
bacteria February 23, 2021 05:15

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Context

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.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding

Network View

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Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adults High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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 https://aopwiki.org/aops/12

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 https://aopwiki.org/aops/17

AOP 281 Acetylcholinesterase Inhibition Leading to Neurodegeneration. Available at https://aopwiki.org/aops/281

AOP 3 Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits. Available at https://aopwiki.org/aops/3

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 https://aopwiki.org/aops/48

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: https://doi.org/10.1101/2020.05.30.125856

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: https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1

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.