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Event: 1739

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Binding to ACE2

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Binding to ACE2
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
receptor binding angiotensin-converting enzyme 2 occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
SARS-CoV-2 leads to acute respiratory distress MolecularInitiatingEvent Young Jun Kim (send email) Open for comment. Do not cite Under Development
Sars-CoV-2 causes encephalitis MolecularInitiatingEvent Anna Price (send email) Under development: Not open for comment. Do not cite Under Development
S glycoprotein, taste impairment MolecularInitiatingEvent Young Jun Kim (send email) Under development: Not open for comment. Do not cite Under Development
Viral spike protein interaction with ACE2 leads to microvascular disfunction MolecularInitiatingEvent Julija Filipovska (send email) Under development: Not open for comment. Do not cite
SARS-CoV-2 causes anosmia MolecularInitiatingEvent Sandra Coecke (send email) Under development: Not open for comment. Do not cite Under Development
Sars-CoV-2 causes stroke MolecularInitiatingEvent Magda Sachana (send email) Under development: Not open for comment. Do not cite Under Development
SARS-CoV2 to hyperinflammation MolecularInitiatingEvent Hasmik Yepiskoposyan (send email) Under development: Not open for comment. Do not cite
SARS-CoV2 to pyroptosis MolecularInitiatingEvent Hasmik Yepiskoposyan (send email) Under development: Not open for comment. Do not cite
Pericytes possess a key role in the heart injury by COVID-19. MolecularInitiatingEvent Evangelos-Panagiotis Daskalopoulos (send email) Under development: Not open for comment. Do not cite
Downregulation of ACE2 causes multi-factorial heart injury and heart failure. MolecularInitiatingEvent Evangelos-Panagiotis Daskalopoulos (send email) Under development: Not open for comment. Do not cite
SARS-CoV-2 leads to intestinal barrier disruption MolecularInitiatingEvent Laure-Alix Clerbaux (send email) Under development: Not open for comment. Do not cite Under Development
ACE2 dysregulation leads to gut dysbiosis MolecularInitiatingEvent Laure-Alix Clerbaux (send email) Under development: Not open for comment. Do not cite Under Development
SARS-CoV-2 leads to infection proliferation MolecularInitiatingEvent Sally Mayasich (send email) Under development: Not open for comment. Do not cite Under Development
SARS-CoV2 to thrombosis and DIC MolecularInitiatingEvent Shihori Tanabe (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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 in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
mouse Mus musculus High NCBI
Mustela lutreola Mustela lutreola High NCBI
Felis catus Felis catus Moderate NCBI
Panthera tigris Panthera tigris Moderate NCBI
Canis familiaris Canis lupus familiaris Low NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult, reproductively mature High
During development and at adulthood High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of the cells (mACE2) in many tissues and in a soluble form form (sACE2).

A table on ACE2 expression levels according to tissues (Kim et al.)

 

Sample size

ACE2 mean expression

Standard deviation of expression

Intestine

51

9.50

1.183

Kidney

129

9.20

2.410

Stomach

35

8.25

3.715

Bile duct

9

7.23

1.163

Liver

50

6.86

1.351

Oral cavity

32

6.23

1.271

Lung

110

5.83

0.710

Thyroid

59

5.65

0.646

Esophagus

11

5.31

1.552

Bladder

19

5.10

1.809

Breast

113

4.61

0.961

Uterus

25

4.37

1.125

Protaste

52

4.35

1.905

ACE2 receptors in the brain (endothelial, neuronal and glial cells):

The highest ACE2 expression level in the brain was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers (Lukiw et al., 2020). High ACE2 receptor expression was also found in the amygdala, cerebral cortex and in the regions involved in cardiovascular function and central regulation of blood pressure including the sub-fornical organ, nucleus of the tractus solitarius, paraventricular nucleus, and rostral ventrolateral medulla (Gowrisankar and Clark 2016; Xia and Lazartigues 2010). The neurons and glial cells, like astrocytes and microglia also express ACE-2.

In the brain, ACE2 is expressed in endothelium and vascular smooth muscle cells (Hamming et al., 2004), as well as in neurons and glia (Gallagher et al., 2006; Matsushita et al., 2010; Gowrisankar and Clark, 2016; Xu et al., 2017; de Morais et al., 2018) (from Murta et al., 2020). Astrocytes are the main source of angiotensinogen and express ATR1 and MasR; neurons express ATR1, ACE2, and MasR, and microglia respond to ATR1 activation (Shi et al., 2014; de Morais et al., 2018).

ACE2 receptors in the intestines

The highest levels of ACE2 are found at the luminal surface of the enterocytes, the differentiated epithelial cells in the small intestine, lower levels in the crypt cells and in the colon (Liang et al, 2020; Hashimoto et al., 2012, Fairweather et al. 2012; Kowalczuk et al. 2008).

 

 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

In vitro methods supporting interaction between ACE2 and SARS-CoV-2 spike protein

Several reports using surface plasmon resonance (SPR) or biolayer interferometry binding (BLI) approaches. to study the interaction between recombinant ACE2 and S proteins have determined a dissociation constant (Kd) for SARS-CoV S and SARS-CoV-2 S as follow,

Reference

ACE2 protein

SARS-CoV S

SARS-CoV2 S

Method

Measured Kd

doi:10.1126/science.abb2507

1–615 aa

306–577 aa

 

SPR

325.8 nM

 

1–1208 aa

14.7 nM

doi:10.1001/jama.2020.3786

19–615 aa

306–527 aa

 

SPR

408.7 nM

 

319–541 aa

133.3 nM

Lan et al., 2020

19–615 aa

306–527 aa

 

SPR

31.6 nM

 

319–541 aa

4.7 nM

doi:10.1016/j.cell.2020.02.058

1–614 aa

306–575 aa

 

BLI

1.2 nM

 

328–533 aa

5 nM

doi:10.1126/science.abb2507

1–615 aa

306–577 aa

 

BLI

13.7 nM

 

319–591 aa

34.6 nM

Pseudo typed vesicular stomatitis virus expressing SARS-CoV-2 S (VSV-SARS-S2) expression system can be used efficiently infects cell lines, with Calu-3 human lung adenocarcinoma epithelial cell line, CaCo-2 human colorectal adenocarcinoma colon epithelial cell line and Vero African grey monkey kidney epithelial cell line being the most permissive (Hoffmann et al., 2020; Ou et al., 2020).  It can be measured using a wide variety of assays targeting different biological phases of infection and altered cell membrane permeability and cell organelle signaling pathway. Other assay measured alteration in the levels of permissive cell lines all express ACE2 or hACE2-expressing 293T cell (e.g. pNUO1-hACE2, pFUSE-hIgG1-Fc2), as previously demonstrated by indirect immunofluorescence (IF) or by immunoblotting are associated with ELISA(W Tai et al., nature 2020). To prioritize the identified potential KEs for selection and to select a KE to serve as a case study, further in-silico data that ACE2 binds to SARS-CoV-2 S is necessary for virus entry. The above analysis outlined can be used evidence-based assessment of molecular evidence as a MIE.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

References

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

de Morais SDB, et al. Integrative Physiological Aspects of Brain RAS in Hypertension. Curr Hypertens Rep. 2018 Feb 26; 20(2):10.

Gallagher PE, et al. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol. 2006 Feb; 290(2):C420-6.

Gowrisankar YV, Clark MA. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. J Neurochem. 2016 Jul; 138(1):74-85.

Hamming I et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7.

Jakhmola S, et al. SARS-CoV-2, an Underestimated Pathogen of the Nervous System. SN Compr Clin Med. 2020.

Lukiw WJ et al. SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell Mol Neurobiol. 2020 Aug 25;1-8.

Matsushita T, et al. CSF angiotensin II and angiotensin-converting enzyme levels in anti-aquaporin-4 autoimmunity. J Neurol Sci. 2010 Aug 15; 295(1-2):41-5.

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

Shi A, et al. Isolation, purification and molecular mechanism of a peanut protein-derived ACE-inhibitory peptide. PLoS One. 2014; 9(10):e111188.

Xia, H. and Lazartigues, E.  Angiotensin-Converting Enzyme 2: Central Regulator for Cardiovascular Function. Curr. Hypertens. 2010  Rep. 12 (3), 170– 175