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Relationship: 2311


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Binding to ACE2 leads to ACE2 dysregulation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Viral spike protein interaction with ACE2 leads to microvascular dysfunction, via ACE2 dysregulation adjacent Julija Filipovska (send email) Under Development: Contributions and Comments Welcome
Binding of S-protein to ACE2 in enterocytes induces ACE2 dysregulation leading to gut dysbiosis adjacent Moderate Laure-Alix Clerbaux (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 Do not cite Under Development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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

This KER summarises the evidence for dysregulation of ACE2 (KE 1854) as a result of its interaction with the viral spike (S) protein of SARS-CoV and SARS-CoV2 (KE1739). This interaction is likely an important aspect of COVID-19 pathogenesis. As the initial step of SARS-CoV2 infection, it is a potential target for intervention at the point of viral entry on cellular level, but also latter for treatment of the disease during viral replication at organism level. In addition,  it is important to summarise exiting evidence for this KER and evaluate the WoE for the prevailing hypotheses that COVID-19 pathogenesis (and hence relevant treatments) is largely governed by the binding of the S protein to ACE2 leading to down-regulation of its physiological function as a protease that converts Angotensin II to Angiotensin 1-7 and hence disturbs the balance within the RAS system. Evidence summary and evaluation should also help identify key data/evidence gaps and inform critical tests and approaches to fill them.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Literature Identification - PubMed Search -initially performed in January 2021 and updated July 2022 using the following search syntax (1): (((SARS-COV[Title/Abstract]) AND (ACE2[Title/Abstract])) AND ((upregulation[Title/Abstract]) OR (up-regulation[Title/Abstract]) OR (downregulation[Title/Abstract]) OR (down-regulation[Title/Abstract]) OR (increase[Title/Abstract]) OR (decrease[Title/Abstract]))) NOT (review)).

Additional targeted search for ACE2 internalisation was performed in April 2021 using search syntax (2): ((ACE2[title/abstract]) AND (internalize)) NOT (review[Publication Type]).

In December 2021, additional serch was performed with the aim to identify evidence for the KER specific for the intestinal tract. The followingg search syntax was used (((((gut[Title/Abstract]) OR (enterocytes[Title/Abstract]) OR (intestinal[Title/Abstract]))) AND (SARS)) AND (ACE2[Title/Abstract])) NOT (review[Publication Type])

Note that the searches are inclusive of both SARS-CoV and CoV2 viruses.

Literature screen - Focused full text screen of literature idenntified by the search (1) [all literature was screened from the initial search [303 references] and only 2022 literature [188 references] was screened from the updated search]: include studies which measure or model any mechanistic aspect of regulation of ACE2 function (mRNA expression, protein expression, emzymatic cativity, shedding) after SARS-CoV2 exposure; exclude reviews and hypothesis papers.

Additional studies identified as follow up on screened references, or identified as relevant from different information channels (e.g. Linkedin), were also included even if they did not appear in the literature initial identification step. For search (2) only focused title screen was done.

Literature analysis of included studies - Analyze the evidence considering different levels of biological organization, time concordance and stressor complexity (whether the study includes recombinant S-protein, non-replicating pseudo virus or replicating virus).

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Aspect of ACE2 dysregulation after S-binding



Empirical evidence Ref.

Molecular level view

ACE2 enzymatic function is dysregulated


Plausibility - Moderate: Enzymatic function of ACE2 as a protease can be affected by allosteric interaction with S-protein by analogy to many other enzymes (Liu & Nussinov 2016; Dutta 2022; Wang DS 2022; Trozzi 2022). However, empirical evidence for ACE2 and other stressors/allosteric modulators is limited, also because not many small molecule inhibitors or activators have been identified. (Important knowledge gap and high priority future research and development]

Empirical evidence - Moderate:  There is empirical evidence that the S proteins (FL or RBD) from both SARS-CoV and SARS-Cov2 S virus which are known to bind to ACE2 with different affinity affect ACE2 enzymatic function. Most evidence shows increase in enzymatic activity (Kcat and/or KM) of ACE2 for different substrates in chemico and in vivo (plasma from infected patients or even recovered COBID19 patients). Relationship to higher effect depending on the S-binding activity is demonstrated (Kiseleva (2021)). Dose dependence is demonstrated (Kiseleva (2021); Jinghua). Not all substrates are affected equally. Most affected is DBAK and not AngII. (Future research need on the structural aspects of ACE2 activity for different substrates, role of ACE2 in KKS vs RAS system, identification and characterisation of ACE2 modulating agents).

One study (Daniell et., al (2022) is inconsistent with the majority (finds decreased ACE2 activity with commonly used pseudo substrate). Further analysis of the assays used (conditions, calculations of activity, substrate concentration/availability) is need to assess the reasons of the inconsistency. Interestingly this study finds increase of the level ACE2 protein itself in the plasma testing system.

Kiseleva (2021) [10.1093/jb/mvab041]

Jinghua Lu (2020) [10.1074/jbc.RA120.015303]

§Reindl-Schwaighofer (2021) [10.1164/rccm.202101-0142LE]

Patel (2021) [10.1183/13993003.03730-2020]

Daniell (2022) [10.1016/j.omtm.2022.07.003]


Cellular/Tissue-Plasma level view

ACE2 protein level is dysregulated


Dysregulation of ACE2 level for the cellular and tissue compartments is dysregulated in a complementary manner

↓ cell membrane

↑ extracellular/interstitium/plasma

Together with the dysregulated enzymatic activity (see section above): important implications for effects on higher organisational levels remain to be explored

Plausibility - High: Cell membrane bound ACE2 is known to be cleaved/shed from the cell membrane by cellular proteases ADAM17/TACE (Liu & Nussinov 2016; Dutta 2022; Wang DS 2022; Trozzi 2022). This shedding effectively downregulates the protein level of enzymatically active ACE2 on the cell surface while releasing the catalytically active ectodomain in the tissue interstitium and plasma. [knowledge gap: significance of ACE2 shedding and cell/tissue distribution of the catalytic activity for function. (ii) role of endocrine, paracrine, hormonal activity of ACE2 catalytic substrates and products]

Empirical evidence - High:  There is extensive and consistent empirical evidence that the S proteins (FL or RBD) from both SARS-CoV and SARS-Cov2 S virus, stimulate ACE2 shedding by its known proteases ADAM17/TACE, but also another protease that also cleaves the S protein itself (TMPRASS).

There is also evidence that ACE2 is internalised into the cell following interaction with recombinant S proteins (FL or RBD) or non-replicating spike protein containing pseudo-SARS-CoV. It is assumed that the ectodomain and its enzymatic activity is also internalised. However there is also evidence which shows that the S-protein is internalised without the ACE2 codomain (Heurich, 2014). The differences in the studies can be explained by closer examination of the experimental conditions, labels and antibodies used (as ACE2 ectodomain is cleaved after interaction with S protein it is important which antibody is used to detect it and where is the label placed when recombinant GFP chimeras are used). Overall, the evidence demonstrates that S protein (and virus by analogy) can enter cells by endocytosis, but it remains to be elucidated how prevalent and pathophysiologically significant this entry mechanism is compared to the membrane fusion mechanism. From the point of view of ACE2 regulation, the latter mechanism together with the consistently observed ACE2 shedding, would imply externalisation and not internalisation of the ACE2 activity following interaction with the virus.

Haga 2008 10.1073/pnas.0711241105

Haga 2010 10.1016/j.antiviral.2009.12.001

Glowacka 2010  10.1128/JVI.01248-09

Patra 2020 10.1371/journal.ppat.1009128

Lei (2021) [10.1161/CIRCRESAHA.121.318902]

Gao X (2022) [10.1016/j.jinf.2022.06.030]

Taglauer (2022) [10.1016/j.ajpath.2021.12.011]

Ackermann (2020) [10.1056/NEJMoa2015432]

Yijia Li (2021) [10.1172/JCI148635]

Reindl-Schwaighofer (2021) [10.1164/rccm.202101-0142LE]

Lundström (2021) [10.1002/jmv.27144]

Wank K. (2022) [10.1161/HYPERTENSIONAHA.121.18295]

El-Shennawy (2022) [10.1038/s41467-021-27893-2]

Mariappan (2022) [10.1016/j.biochi.2022.06.005]

Taglauer (2022) [10.1016/j.ajpath.2021.12.011]

Daniell (2022) [10.1016/j.omtm.2022.07.003]

Patel 2021 10.1183/13993003.03730-2020

Raghavan (2021) -10.3389/fcvm.2021.687783

Gorshkov 2022 - 10.1021/acsnano.0c05975

Inoue, 2007 - 10.1128/JVI.00253-07

Wang H., 2008 -10.1038/cr.2008.15

Wang S., 2008 -10.1016/j.virusres.2008.03.004

Heurich, 2014 -10.1128/JVI.02202-13

Cellular level view

Ace2 mRNA level is dysregulated


↓ ?

Plausibility - Moderate: ACE2 is an ISG and is differentially expressed in may systems relevant to viral replication and innate immune response. However there is no evidence (to my knowledge) that ACE2 itself, after binding to its substrates can initiate intracellular signalling that would lead to differential mRNA expression. It is plausible however, that ACE2 dysregulation can modulate mRNA expression from number of genes (including the ace2 gene itself) indirectly via the resulting dysregulation of levels of its substrates, products and their effect on their receptors. Hence the  “moderate” call. It is not highly plausible, although not impossible that direct S-binding (independent of replication/ persistency of the stress) can lead to Ace2 mRNA dysregulation.

Empirical evidence – Moderate (related to direct S-binding): There are number of studies reporting that exposure to the Spike protein, non-replicating pseudoviruses or replicating viruses can be associated with differential expression of Ace2 mRNA in different tissues or interstitial fluids (e,g BALF, saliva, nasopharyngeal swabs). However, the evidence appears conflicting in terms of the direction of the dyregulation. Both up and down regulation are reported and no obvious pattern emerges yet as to the critical factor for the two types of regulation (tissue or fluid type; in vitro/in vivo; replicating/non-replicating stressor; time of measurement after stress; presence of dead vs infected v.s bystander cells etc.). Further analysis of the details of the test systems is needed to elucidate the underlying aspects of the apparent inconsistences and conflicting evidence in test systems other than the GI tract (see Uncertainties and Inconsistences section for the relevant analysis in the GI tract).

Li (2020) [10.1016/j.bbrc.2020.04.010]

Lieberman (2020) [10.1371/journal.pbio.3000849]

Feng (2020) [10.3389/fmolb.2020.568954]

Garvin (2020) [10.7554/eLife.59177]

Lee (2020)  [10.1080/22221751.2020.1827985]

Heuberger (2021)  [0.15252/emmm.202013191]

Lamers  (2020) [10.1126/science.abc1669]

¥Taglauer (2022) [10.1016/j.ajpath.2021.12.011]

*Khan (2022) [10.1093/cvr/cvac097]

*Pistollato (2022) [10.1016/j.reprotox.2022.04.011]

Nataf & Pays (2021) [10.3390/ijms221910440]

Triana (2021) [10.15252/msb.202110232]

@Volbeda (2021) [10.1186/s13054-021-03631-4]

^Gao X (2022) [10.1016/j.jinf.2022.06.030]

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Angiotensin-converting enzyme 2 (ACE2) is a transmembrne protein which under normal physiological conditions acts as a carboxypeptidase with broad substrate specificity. Angiotensin II is recognised as the main substrate of ACE2, but ACE2 hydrolyses a number of other biologically active peptides including DABK, apelin-13, neurotensin(1–11), dynorphin A-1–13), β-casomorphin-(1–7), and ghrelin (Vickers 2002, Humming, 2007). Hence, ACE2 is one of the major regulating enzymes in the local tissues and systemic plasma RAS and KKs systems, mainly balancing the action of its homologue ACE.

In the gut, ACE2 interacts with the Broad Neutral (0) Amino Acid Transporter 1 (B0AT1) (Slc6a19) and chaperons its membrane expression. As B0AT1 mediates the uptake of neutral dietary amino acids, such as tryptophan and glutamine, into intestinal cells (Camargo, 2009), ACE2 is indirectly involved in regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the gut microbiome (Camargo, 2020, Hashimoto, 2012).  

Considering the above, it is plausible that interference with any aspect of the ACE2 expression, it’s enzymatic or B0AT1s-shaperone function represents a potential target for dysregulation with a wide range of downstream effects.

ACE2 is not known to act as a classical receptor that would itself initiate intracellular signalling cascades after binding of ligands or substrates and very few selective inhibitors or stimulators of its activity are available to study the effects of potential stressors and modulators of ACE2.  However, binding of SARS-CoV and SARS-CoV2 spike protein to ACE2 has been demonstrated (refs from Event: 1739) and this interaction represents an essential step for viral entry into the cells (refs from Event: 1738).

How interaction of ACE2 with the spike protein (KE upstream) perturbs ACE2 function (KEdownstream) is evaluated in the empirical evidence section of this KER.

At a molecular level, it is plausible that binding of the spike protein to the extracellular domain of ACE2 may perturb the catalytic activity of both, the cell membrane mACE2 or the cleaved catalytically active ectodomain sACE2, by allosteric interaction with the catalytic site (Liu & Nussinov 2016; Dutta 2022; Wang DS 2022; Trozzi 2022).

Interaction with spike protein may also perturb the shedding of ACE2 catalytic ectodomain. ACE2 is constitutively cleaved (shed) mainly by another membrane bound metalloprotease ADAM17, also known as TACE, TNFalpha Converting Enzyme (Zunke 2017) in a number of cells and tissues (Guy 2008 in human cardiac myofibroblasts; Peng Jia, 2009 in human lung epithelial cells and BALF; Werner, 2005 in canine epithelial polarised kidney MDCKII cells stabilly expressing ACE2; Iwata, 2009 in Chinese Hamster Ovary Cells). The exact role of constitutive ACE2 shedding is not well understood, but proteolytc ectodomain shedding of membrane proteins is a fundamental post-translational regulatory mechanism of the activity/function of a wide variety of proteins, including growth factors, cytokines, receptors and cell adhesion proteins (Lichtenthaler et al., 2018).

Binding of the spike (S) protein from both SARS-CoV has been associated with cleavage of the ACE2 ecodomain by TACE/ ADAM17 (Haga 2008, Haga 2010, Jocher, 2022), but also by another host protease TMPRASS2 (Heurich, 2014; Shula 2011) which also cleaves the Spike protein itself thus mediating viral entry by fusion of the cellular and viral membranes.  Spike protein mediated ADAM17 shedding of ACE2 has not been demonstrated for SARS-CoV2 (to my knowledge). However, the interplay between spike and these proteases has been suggested as critical and linked events based on analogy and also some structure-function considerations (Schreiber 2020; Heasly 2022; Zipeto 2020).  It is plausible then, that the spike induced shedding of ACE2 (via ADAM17 or other proteases) perturbs the distribution of the catalytically active mACE2/sACE2 and consequently differentially dysregulates ACE2 function/activity locally and systematically (Wysocki 2010). This in turn would have significant implications for the development of therapies that would target ACE2 activity and the RAS system appropriately in terms of delivery and timing.

Additionally, it is plausible that membrane bound ACE2 is down-regulated due to endocytosis of viral particles as suggested by earlier studies with SARS-CoV spike protein (Inoue, 2007; Wang H., 2008; Wang S., 2008) but also with SARS-CoV2 spike protein (Raghavan 2021, Gorshkov 2022). The relative contribution of the membrane fusion versus endocyitic route varies for the two SARS-CoV viruses (CoV1 and CoV2). This difference has been suggested as an important aspect of the differential infectivity and transmissibility of the two viruses (Zhu, 2021). It may also affect the relative magnitude and direction of mACE2 and sACE2 dyregulation.

Finally, transcriptional dysregulation of ACE2 mRNA synthesis is also plausible, but the process is not likely to be an immediate consequence of spike binding to ACE2, but rather requires some downstream signalling (potentially other intermediate KEs)and time for the biosynthesis of the mRNA and protein. Consistent with this, there is evidence that Ace2 (human but not the mouse), is an Interferon Stimulated Gene (ISG) activated also by some other viruses, inflammation, hypoxia and Synthetic dsRNA, poly(I:C) (Ziegler, 2020, Smith, 2020; Salka 2021, Zhuang 2020). However, it emerges that interferons and viruses stimulate a particular truncated form of ACE2, the dACE2 and not the full length ACE2 (Onabajo 2020; Scagnolari, 2021; Blume, 2021; Oliveto, 2022). The significance of this (post?)transcriptional modulation of Ace2 mRNA is not clear, and the enzymatic activity of the product of the alternatively spliced or, Ace2 mRNA initiated from a different promotor (which contains the catalytic domain but not the spike protein binding site) has not been examined. In addition, there is some evidence that S-protein binding can also lead to (direct?) suppression of ACE2 and Type I Interferon synthesis. To facilitate the analysis of the WoE for relevant perturbation of ACE2 as related to mRNA synthesis following the interaction with SARS-CoV and SARS-CoV2 spike protein, existing empirical evidence is outlined in the KER highlighting considerations for stressor type and time concordance between the two KEs.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Evidence Collection Strategy

The literature search is not comprehensive or systematic and needs continuous improvement.

In all of the studies reviewed here, ACE2 dysregulation following exposure to recombinant S-protein and replicating virus is considered as equivalent for the prpose of evaluationg ACE2 dysregulation. However, it should be noted that the literature screening step showed that inflammation and exposure to other stressors (nanomaterials and other viruses, like influenza) were also associated with ACE2 dysregulation, indicating that aspects of the stressor multiplication and/or persistency, additional to the S-protein binding, may be responsible for the observed ACE2 dyregulation. These references were tagged but not further analysed and not included in this KER that is focused on S-protein binding. They can be informative if this KER is eventually modified and potentially split into two: (i) direct/adjacent KER (studies examining ACE2 dysregulation after direct and short term exposure to S-protein binding or non-replicating pseudoviruses) and (ii) indirect/nonadjacent KER (studies with replication virus and persistent infection).

Focus on GI tract relevant evidence (published in

Both ACE2 down and up regulation are observed in the gut as in the other test systems (see gut unreated evidence table). The apparent inconsistences regarding the direction and magnitude of ACE2 dysregulation in the different studies may reflect the dynamic, temporal components of the dysregulation driven not only by the interaction of ACE2 with the surface viral components i.e. S-protein binding, but also by the interaction of the replicating viral components with the innate immunity response elements, particularly in the test systems with replicating viruses used with the GI-tract-derived organoids.

ACE2 mRNA down-regulation in SARS-COV2 treated GI-derived organoids is reported in one study using scRANseq analysis (Triana et al., (2021). The down-regulation was specific to enterocytes actively replication the virus. Another study Nataf & Pays (2021) also reports profound but transient ACE mRNA down regulation.

Evidence for SARS-COV2 mediated up-regulation of ACE2 mRNA in GI-tract derived organoids is also available (Lamers et al., 2020; Lee at all (2020); Heuberger et al., 2021) and consistent with the similar studies in many other tissue/organ systems (see evidence table for other organs above). This is also consistent with the finding that ace2 is an Interferon Stimulated Gene (IFG) in airway epithelial cells (Ziegler, 2020) and also in colon enterocytes (Heuberger et al., 2021). In fact, all there studies also demonstrate a time concordance of ACE2 mRNA up-regulation with stimulation of ISG response in the infected organoids (Lamers et al., 2020; Lee at all (2020); Heuberger et al., 2021). Interestingly, even the scRNAseq study by Triana et al., 2021 which zoomed on specific cells within the organoid found that SARS-COV2 treatment induced distinct proinflammatory and ISG expression profiles in infected and bystander cells in the organoid. Namely, expression of interferon-stimulated genes was pronounced in bystander cells, while the infected cells showed strong NFkB/TNF-mediated pro-inflammatory response but a limited production of ISGs, suggesting that while SARS-CoV-2 may activate ISG by paracrine signaling, it may suppress the autocrine action of interferon i.e inducton of IGS including ACE2 in infected cells. This would be consistent with down-regulation of ACE2 in the infected cells observed in this study. In addition, this may explain why in some studies down-regulation of ACE2 mRNA can be observed under certain conditions (e.g. bulk mRNA measurements) and at some (earlier) time points of replication. Furthermore, the relationship of an observed increase of ACE2 mRNA to dysregulation at protein and enzymatic level remains to be elucidated. Indeed, most recently Harnik et al. 2021 (10.1038/s42255-021-00504-6) examined the spatial discordances between mRNAs and proteins in the intestinal epithelium and their significance for interpretation of transcriptomic data. Such apparent discordances have also been reported in the heart and lung tissue in mice and human (KE1854).

Identification of alternative forms of ACE2 mRNA and protein, an N-terminus truncated dACE2, which appears to have distinct transcriptional regulation profile compared to flACE2 (Onabajo et al, 2020, Janakowski et al (2021) - 0.1016/ j.isci.2021.102928) may also account for some of the observed inconsistences. However, a detailed analysis of experimental conditions in past, and careful design of probes and primers in future studies is necessary. Interestingly, concomitant down and up regulation of 97kD and 80kD anti-ACE2 polyclonal Ab-reacting proteins has been detected in differentiating human colon adenocarcinoma cell line HT29 (Bártová et al. (2020) 10.18632/aging.202221). Considering only one form of ACE2 relevant (97KD the only form detected in HEK293 and A549), the authors conclude that ACE2 is down-regulated in mature differntiatiatiated enterocytes compared to undifferentiated ones. This is in contrast to all mRNA and even cytoimmunostaining studies described above which demonstrate that a highest level of ACE2, both mRNA and protein is detected in the mature enterocytes and at the brush borders of the intestine and 3D organoids (eg. Lamers et all., 2020, Lee et al., 2020; Hauberge et al., 2021; Triana et al., 2021). Notably, the initial analysis by Onabajo et al, 2020 found that dACE2 mRNA is enriched in in squamous tumors of the respiratory, gastrointestinal and urogenital tracts.

The uncertainties and uncosnstances disused above illustrate clearly the need for careful characterization of the test systems to facilitate robust interpretation of the results.

In addition, we note that to date (to our knowledge), the majority of studies related to SARS-COV2-mediated ACE2 dysregulation, focus on ACE2 mRNA expression while structural/protein and functional studies are lacking, particularly in the gastro intestinal system. The novel gut-derived organoid systems can help address this gap by monitoring level and cell distribution of ACE2 protein as well as its function as B0AT1chaperon, via monitoring the membrane expression and/or the transporter function of B0AT1 itself. In addition, treatment with S-protein and/or non-replicating SARS-COV2 pseudo-viruses [Minghai & Zhang (2021) 10.7150/ijbs.59184], may help address better any potential direct effect of S-binding on ACE2 dysregulation. Finally, a development of more complex organoid systems that would also include microbiota or elements of the immune and/or vascular system are needed to better examine ACE2 dysregulation by SARS-COV2 but also the effects of such dysreulation at higher organizational level and in conjunction with the other elements of the RAS system.

Finally, evidence on up- or down-regulation of ACE2 in the GI tract of SARS-COV infected patients is not available to our knowledge. Examining the GI specific transcriptomic, proteomic and biomarker databases of COVID19 patents may help address some of these uncertainties.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)


both male and female sex (XX and XY chromosomes)

ACE2 localizes to the X sex chromosome, displaying higher expression in female than in male tissues [1], contributing to explain why women have milder disease progression. Lower levels of ACE2 in SARS-CoV-2 patients has been associated with higher rates of severe outcomes [2]. In particular, ACE2 is involved in the protection of acute lung injury [3], as reduction in ACE2 levels after infection has been associated with severe lung injury [4]. Because females have higher ACE2 levels, presumably more ACE2 remains available after viral entry and impairs severe lung and cardiac manifestation.

1. doi: 10.1177/1933719115597760

2. doi: 10.3390/ijms21082948

3. doi: 10.1038/nature03712

4. doi: 10.1038/nm1267


(weak evidence)


One study showed that PFOA upregulates ACE2 expression in lungs [1].

1. doi: 10.1016/j.toxrep.2021.11.014

Vitamin D moderate evidence)

Vit D deficiency

ACE2 is expressed in the human vascular endothelium and the respiratory epithelium [1]. VDR is also highly expressed in the lung tissue [2]. The effect of vitamin D and VDR on RAS occurs via both induction of ACE2/Ang (1-7) and the vasoactive Mas Receptor axis activity and inhibition of renin and of the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang (1–7) [3]. Thus, vitamin D and VDR exert a vasorelaxant, anti-hypertensive modulation of the axis. Supportive evidence is provided by a VDR agonist, calcitriol, that down-regulated RAS activation in a rat model of acute lung injury [2]. The association of low vitamin D status with overactivation of RAS regulated by ACE2 has been observed also in non-infectious diseases [4]. Therefore, low vitamin D status, through a reduced VDR ligand, supports ACE2 dysregulation and ACE2/ACE imbalance, directly impacting the endothelium of lung vessels [5].

1. doi: 10.3390/cells9071652

2. doi: 10.3892/mmr.2017.7546

3. doi: 10.1002/rmv.2119

4. doi: 10.1016/j.jsbmb.2021.105965

5. doi: 10.1007/s10456-021-09805-6

Genetic factors

Currently, many studies focus on the impact of ACE2 SNPs that alter its expression level. However, SNPs that facilitate binding to S protein have not been inspected in a systematic and genome-wide manner. Many authors have postulated that SNPs in the ACE2 gene (Xp22.2) could affect the binding affinity of SARS-CoV-2 [1]. Altered binding between ACE2 and the S protein is expected to affect the RAS cascade, but no conclusive evidence has been identified so far.

1. doi: 10.1097/FPC.0000000000000436

Pre-existing heart failure


The dysregulation of ACE2 and of the RAS system is a characteristic of several cardiovascular pathologies having detrimental inflammatory effects, both locally (in the heart) and systematically [1].

Recently, evidence showed that the S protein itself has profound effects on the normal functioning of the cardiac pericytes also by non-infective mechanisms, e.g., by stimulating the pericyte-mediated release of pro-inflammatory factors that can lead to endothelial cell death [2].



Diet Several dietary compounds impact the ACE axis

Many proteins found in seaweed have ACE-inhibiting properties and are thought to shift the balance of RAS towards the less inflammatory ACE2/Ang (1-7)/MAS axis [215]. Resveratrol, a stilbene compound found in several plant foods, appears to be able to promote this pathway as well, as it was found in multiple in vitro and in vivo studies to decrease the expression of angiotensinogen, ACE, and AT1R, and increase the expression of the AT2R and Mas receptor [206,216].

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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