Binding to ACE2

PR:000003622

PR angiotensin-converting enzyme 2

GO:0005102

GO receptor binding

GO:0009299

GO mRNA transcription

GO:0004180

GO carboxypeptidase activity

GO:0034394

GO protein localization to cell surface

WIKI occurrence

WIKI increased

WIKI decreased

Sars-CoV-2 Virus from the coronaviridae family related to SARS-CoV, 229E, NL63, OC43, HKU1 and MERS.

Transmitted by aerosols

2021-02-23T04:50:40

2022-09-09T05:09:36

SARS-CoV

2020-03-01T10:42:46

Influenza Virus

2021-12-05T12:32:16

9606

NCBI Homo sapiens

10090

NCBI mouse

9666

NCBI Mustela lutreola

9685

NCBI Felis catus

9694

NCBI Panthera tigris

9615

NCBI Canis familiaris

9544

NCBI rhesus macaques

9541

NCBI cynomolgus monkeys

10090

NCBI Mus musculus

Binding to ACE2

Molecular

Angiotensin-converting enzyme 2 (<a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE2">ACE2</a>) 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.) <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:medium none; height:806px; width:1049px"> <tbody> <tr> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:146px">   </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:146px"> Sample size </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:147px"> ACE2 mean expression </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:147px"> Standard deviation of expression </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Intestine </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 51 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 9.50 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.183 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Kidney </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 129 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 9.20 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 2.410 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Stomach </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 35 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 8.25 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 3.715 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Bile duct </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 9 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 7.23 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.163 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Liver </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 50 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 6.86 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.351 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Oral cavity </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 32 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 6.23 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.271 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Lung </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 110 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.83 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.710 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Thyroid </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 59 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.65 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.646 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Esophagus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 11 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.31 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.552 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Bladder </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 19 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.10 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.809 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Breast </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 113 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.61 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.961 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Uterus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 25 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.37 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.125 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Protaste </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 52 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.35 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.905 </td> </tr> </tbody> </table> 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).

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, <table cellspacing="0" class="Table" style="border-collapse:collapse; width:568px"> <tbody> <tr> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:28px; width:176px"> Reference </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:102px"> ACE2 protein </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:140px"> SARS-CoV S </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:151px"> SARS-CoV2 S </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:128px"> Method </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:156px"> Measured Kd </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1126/science.abb2507" rel="noopener" target="_blank">10.1126/science.abb2507</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–577 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 325.8 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 1–1208 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 14.7 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1001/jama.2020.3786" rel="noopener" target="_blank">10.1001/jama.2020.3786</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 19–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–527 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 408.7 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–541 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 133.3 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> <a href="https://elifesciences.org/articles/61390#bib67" style="color:blue; text-decoration:underline">Lan et al., 2020</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 19–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–527 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 31.6 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–541 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 4.7 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1016/j.cell.2020.02.058" rel="noopener" target="_blank">10.1016/j.cell.2020.02.058</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–614 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–575 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> BLI </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 1.2 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 328–533 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 5 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1126/science.abb2507" rel="noopener" target="_blank">10.1126/science.abb2507</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–577 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> BLI </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 13.7 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–591 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 34.6 nM </td> </tr> </tbody> </table> 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.

The KE is applicable to broad species/life stage/sex. The binding of ACE2 occurs in the cells which express ACE2.

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Mixed

High

Adult, reproductively mature

High

During development and at adulthood

High High High Moderate Moderate Low

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 AOPWiki 2020-03-02T03:18:47

2024-10-21T02:25:03

Dysregulation, ACE2 expression and activity

ACE2 dysregulation

Molecular

The angiotensin-converting enzyme 2 (ACE2) is a membrane-anchored protein with wide tissue distribution <a href="https://www.proteinatlas.org/ENSG00000130234-ACE2" style="color:#0563c1; text-decoration:underline">https://www.proteinatlas.org/ENSG00000130234-ACE2</a>. ACE2 has multiple functions, and is highly regulated at the transcriptional, post-transcriptional and post-translational levels. Modulation of the expression levels or functional activity of the ACE2 receptor is described in this KE.  ACE2 is bound to cell membranes, and in polarized cells it is exclusively targeted to the apical surface (Werner 2005; Ren 2006) [for more detailed description of the expression patterns of ACE2 see the applicability domain section].   ACE2 FUNCTIONS Enzymatic function of ACE2 in interlinked bioactive peptide systems ACE2 is mainly known and studied as a type I ectoenzyme i.e. a transmembrane protein with an extracellular amino-terminal domain harbouring a carboxypeptidase active site.  ACE2 cleaves the carboxyterminal amino acid from a number of biologically active peptides (Figure 1 and 2), thus activating or deactivating them as agonists within the Renin Angiotensin System (RAS) (Santos et al., 2019) and within the Kinin–kallikrein system (KKS) (Kakoki & Oliver, 2009) in mammals. The extracellular domain of ACE2 can itself be cleaved (shedding) in vitro and in vivo, releasing a soluble and catalytically active sACE2 (Guy et al., 2008 in human cardiac myofibroblasts; Peng Jia et al., 2009 in human lung epithelial cells and BALF; Werner et al., 2005 in canine epithelial polarised kidney MDCKII cells stabilly expressing ACE2). Constitutive shedding of ACE2 from the cellular membrane is mediated by another membrane-bound metalloprotease from the adamalysin family, ADAM17 (Iwata et al., 2009) also known as TACE, TNFalpha Converting Enzyme (Zunke 2017).  Other proteins may also be involved in ACE2 protolithic modulation (Lambert et al, 2008). The exact role of ACE2 shedding in modulating its function is not well understood, however, being catalytically active, the released sACE2 can, as the membrane-anchored full length ACE2, generate biologically active peptides which activate specific receptors in different cells/tissues/organs. Thus, the ACE2 function in the organism is mediated via its peptide products activating specific receptors on the same, (autocrine), nearby (paracrine) and potentially distant cells. <a name="_heading=h.gjdgxs"></a>      ACE2 is a homologue of angiotensin-converting enzyme (ACE), with whom it shares significant sequence similarity (Tipnis, 2000; Donoghue 2000), yet exhibits very distinct enzymatic activity. ACE2, as ACE, is a zink-metallopeptidase, however ACE2 is strictly a carboxypeptidase while ACE is an dipeptidase. Furthermore, the main substrate of ACE2 is the octopeptide Angiotensin II (Ang II), the enzymatic product of its homologue ACE. By cleaving a single amino acid from the C-terminus of Ang II, ACE2 generates a functionally different bioactive peptide Angiotensin 1-7 (Ang1-7) (Figure 1). ACE2 is key to the regulation of local and systemic Ang II levels. Ultimately, the function of ACE2 at tissue level is mediated via the interaction of its main active product Ang1-7 with the Angiotensin II receptor 2 (AT2R), balanced by the activity of its homologue ACE and other peptidases in the RAS.         Figure1: Enzymatic activity of ACE2 compared to its homologue ACE and another protease relevant to the RAS (from Rice et al., 2004) [to add] Figure 2: Simplified representation of the biological function of the enzymatic products of ACE2 activity in the KKS (adopted from Kakoki & Oliver, 2009). [to add] Although most studies have focused on the role of ACE2 in angiotensin metabolism in the RAS, the enzyme has broad substrate specificity and it also hydrolyses a number of other biologically active peptides including des-Arg9-bradykinin (DABK), apelin-13, neurotensin(1–11), dynorphin A-1–13), β-casomorphin-(1–7), and ghrelin (Vickers 2002, Humming, 2007. ACE2 cleavage of DABK to bradykinin 1-7 (Figure 2) has been demonstrated in chemico (Donoghue 2000, Vickers 2002), with human polarised primary lung cells in vitro and in mice broncho-alveolar lavage (BALF) (Sodhi 2018). Deactivation of DBAK, a preferencial bradikynin receptor 1 (B1K) agonist (Coulson et al., 2019), is an important regulatory function of ACE2 in the KKS (Figure 2). 1.2   ACE2 chaperone function for transporters of amino acid transfer (B0AT1) Somewhat less known is the RAS independent function of ACE2 in the gut, where it  regulates intestinal amino acid homeostasis, expression of antimicrobial peptides, and the gut microbiome (Camargo et al., 2020). ACE2 was identified as an important regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis in mice (Hashimoto et al., 2012).  The mechanism by which ACE2 regulates amino acid transport in the intestine involves interaction with the broad neutral (0) amino acid transporter 1 (B0AT1) (Slc6a19) which mediates the uptake of neutral dietary amino acids, such as tryptophan and glutamine, into intestinal cells in a sodium-dependent manner (Camargo et al, 2009).   A crystal structure study revealed a complex dimer of ACE2/ B0AT1 heterodimers (Yan et al., 2020), previously suggested by immunoprecipitation of intestinal membrane proteins in mice (Fairweather et al., 2012). Immunofluorescence showed co-localization of B0AT1 with ACE2 at the luminal surface of human small intestine (Vuille-dit-Bille et al., 2015).  ACE2 seems to be necessary not only for the amino acid transfer by B0AT1, but also for its membrane expression (Camargo et al., 2008; Hashimoto et al., 2012).      REGULATION OF ACE2      LEVELS and ACTIVITY ACE2 is regulated at the transcriptional, post-transcriptional and post-translational level, the final potentially differing in the different organisational contexts: cell membrane versus tissue (plasma and/or interstitial). In addition, all of these regulatory processes may be differentially modulated in different tissues. Age, sex and species specific differences in aspects of the regulation, and also tissue specific regulation, have been reported (reviewed in Saponaro 2020). Loss of function of ACE2 in vivo in ACE2 knockout (KO) mice has been associated with elevated levels of Ang II in heart, kidney and plasma as well as histological and functional perturbations in the lungs and in the cardiovascular (Crackower et al, Nature 2002) and renal (Oudit et al, 2010) systems, mostly in the presence of a particular stress factor, in some cases potentiated by aging (reviewed in Humming 2007). Furthermore, Ace2 KO mice exhibited reduced serum levels of tryptophan, together with downregulated expression of small intestinal antimicrobial peptides and altered gut microbiota, which was re-established by tryptophan supplementation (Hashimoto et a., 2012).   At transcriptional level Overall, the transcriptional regulatory elements of the ace2 gene are not well characterised. Ace2, human but not mouse, was identified as an Interferon Stimulated Gene (ISG) in airway epithelial cells (Ziegler, 2020), indicating species specific regulation and its importance for human viral infections mediated via ACE2 (e.g. SARS-COV2). Influenza virus infection also induced ACE2 mRNA synthesis in human lung tissue (Ziegler, 2020). In vitro in normal kidney tubular epithelial cell line (HK-2) ACE2 mRNA is down-regulated following Ang II treatment (Koka 2008). The exact transcriptional regulatory mechanism is not clear, but the observed ACE2 mRNA up-regulation in this system appears to be mediated by the activation of the ERK1/2 and p38 MAP kinase pathway and dependent on the activation of AT1R receptor by AngII, as demonstrated by specific AT1R, MAP kinase and ERK1/2 MAP kinase inhibitors (Koka et al., 2008). Regulation of ACE2 expression mediated by AT1R activation is an important endogenous regulatory mechanism for ACE2 activity within the RAS system (ref…..). Vitamin D Receptor (VDR) may also emerge as an ACE2 transcriptional regulator/repressor (Saponaro 2020 and Glinsky 2020, unreviewed pre-print). VDR has already been implicated in the transcriptional repression of Renin, at least in vitro (Yuan 2007). 17b-estradiol (E2) has also been indicated in the transcriptional regulation of ace2 in a tissue specific manner (recently reviewed by Saponaro 2020). E2 down-regulated ace2 transcription particularly in kidney and differentiated airway epithelial cells. However, in human atrial tissue, E2 appeared to up-regulate ACE2 mRNA and protein. This change was associated with decreased levels of ACE homologue protein. The exact mechanism for this regulation remains to be elucidated as it may represent a significant modulating factor in the differential sex susceptibility to ACE2 dysregulation under varied stress conditions (e.g SARS-COV infection). Epigenetic transcriptional regulation of ace2 has also been indicated (recently reviewed by Saponaro 2020. Transcription of ace2 is repressed by histone methylation and stimulated by NAD+-dependent deacetylase SIRT1 during cellular energy stress. Interestingly, in children ACE2 is normally hypermethylated and poorly expressed in the lung and in other organs (Saponaro 2020, ref therein). Gut microbiota have also been implicated in the transcriptional regulation of ACE2 expression in the gut (Yang et al., 2020) but also in the lung (Koester et al., 2021). Whether this is directly or indirectly occurring via microbial metabolites remains to be elucidated, but the study by Koester ar e al, 2020 observed variability in intestinal Ace2 expression in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. At post-transcriptional level Generally, modulation of ACE2 mRNA and protein levels appear to follow consistent pattern. However, it has been demonstrated that under certain conditions and in some tissues, mRNA and protein levels appear to follow a different pattern, suggesting important role of post-transcriptional or post-translational (see next section) regulation of ACE2 expression and function. For example, hypertension in humans has been associated with different modulation of mRNA and protein levels in the heart tissue (Koka 2008). Specifically, heart tissue from patients with hypertension showed decreased levels of ACE2 mRNA while protein levels were comparable to normal tissue. In contrast, ACE mRNA and protein levels appeared consistently up-regulated in hart tissue of hypertensive patients (Koka 2008).  In the same study, in the kidney tissue from patients with hypertensive nephropathy, both, ACE2 mRNA and protein levels, appeared consistently down-regulated compared to normal kidney tissue (Koka 2008). Significant suppression of ACE2 mRNA and protein expression was also observed in vitro in normal kidney tubular epithelial cell line (HK-2) treated with AngII (linked to hypertension in vivo) in a dose and time dependent manner Koka 2008).  AngII treatment in vitro with myocardia- derived cells was not examined in this study and the discrepancy of mRNA and protein level modulation in the hypertensive human heart tissue biopsies was attributed by the authors to limitations of the detecting methods (Koka 2008). Clear discrepancy in the modulation of mRNA versus protein level has been observed in vivo in mice in myocardial tissue (Patel 2014).  Namely, up-regulation of mRNA synthesis was associated with down-regulation of ACE2 protein levels following 1 or 2 week treatment by exogenous circulating AngII (Patel 2014). In this study, down-regulation of ACE2 protein levels was alleviated by AT1R blockage/inhibitors, while mRNA up-regulation was not dependent on AT1R signalling. This strongly suggests involvement of post-transcriptional mechanism step(s) mediated by AngII/AT1R fot the regulation of ACE2 protein/function, at least in myocardial tissue under certain stress conditions. Modulation of ACE2 protein and activity levels by AngII is clinically relevant phenomenon and AngII activity blockers (ACE inhibitors and AT1R blockers) are used to move the balance of the RAS from the ACE/AngII/AT1R axis towards the protective ACE2/Ang1-7/MasR axis. This is particularly relevant in the lung where ACE/ACE2 activity ratio is high (Roca-Ho, 2017-mice, human and other ref……?..). The up-regulation of ACE2 mRNA observed in mouse myocardial tissue by Patel et al., 2014 appears contradictory to the finding of ACE2 mRNA down-regulation observed in the heart of hypertensive patients observed in the study of Koka et al., 2008 (if the latter result is accepted despite potential method limitations). However, it should be noted that the base level of ACE2 and also the relative ACE2/ACE ratio in the case of chronic hypertensive patients, many of whom have been on AT1R inhibitor treatment (Koka 2008), and in healthy mice treated with AngII for relatively short time (Patel 2014), may be different leading to response to the stressor (hypertension and AngII) over time. Consistent with this, distinct ACE/ACE2 activity ratios have been demonstrated  in different organs of normal, non-obese diabetic (NOD) and insulin treated NOD  mice, which varied additionally over the time course after the onset of diabetes (Roca-Ho et al., 2014). Finally, species specific regulatory differences may be involved that would warrant further examination. But, overall, the studies discussed above illustrate the complex regulatory mechanisms of ACE2 mRNA, protein and activity levels in different tissues and under different stress conditions for the RAS system. Rapid and transient up-regulation of ACE2 mRNA followed by down-regulation of ACE2 protein levels has been reported in the lung as a result of LPS induced acute inflammation in mice (Sodhi 2018). In this case the increase of ACE2 mRNA appears to be a rapid and transient compensatory effect to ACE2 protein/activity down-regulation mediated by NFk- B signalling in response to acute inflammation. Inhibiting NF- B signaling by Bay11-7082 restored ACE2 activity, again demonstrating post transcriptional or translational regulation of ACE2 in the lungs. In addition, this study examined the effect of ACE2 dysregulation on the KKS and demonstrated that attenuation of ACE2 activity under conditions of LPS induced inflammation leads to impaired DABK inactivation and enhanced BKB1R signalling (Sodhi 2018). The underlying mechanisms of post-transcriptional mRNA regulation remain to be elucidated further. There is evidence that small non-coding micro RNAs (miRNA or miRs) may be involved  (Widiasta 2020; Lu 2020; Fang 2017, Lambert 2014 ). At post-translational level – enzymatic activity including shedding Complexity of analysing the regulation of ACE2 function is emphasized even further when enzymatic activity is considered, including its spatial distribution between cell/tissue versus interstitium/plasma, mediated by shedding. The exact role of ACE2 shedding is not well understood, but proteolytic 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). sACE2 activity is increased in patients with heart failure (HF) and correlates with disease severity (Epelman 2008). In mice in vivo, shedding of ACE2 by TACE was induced by sub-chronic (2 weeks) exogenous AngII treatment (mimicking HF), leading to decreased ACE2 protein level and increased ACE2 mRNA in myocardial tissue with concurrent elevated sACE2 activity (Patel et al., 2014).

ACE2 activity <ul> <li>using fluorescently  labeled peptide substrates (Rice, 2004; Sodhi, 2008; Roca-Ho, 2017 1; Lu and Sun, 2020; Xiao 2017) </li> <li>measuring catalytic products (direct) or markers of activation of receptors for the products (indirect) of ACE2 activity (e.g Ferrario 2005)</li> </ul>   ACE2 levels <ul> <li>mRNA by RT-PCR (Sodhi 2018; Roca-Ho, 2017) or scRNA seq (e.g. Qi. et al 2020)</li> <li>protein in tissue extracts/preparations by immunoprecipitation or Western blotting (Koka 2008)</li> <li>protein in live tissues or cultured cells by immunostaining (Humming 2007; Fraga-Silva et al., 2011; Ren 2006; Warner 2005)</li> </ul> high throughput and quantitative measurement of protein by quantitative proteomic analysis (Park 2020;  Stegbauer 2020)

<table cellspacing="0" class="Table" style="border-collapse:collapse; width:616px"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:616px"> ACE2 is expressed in a wide variety of tissues affecting their function. ACE2 was initially identified in human lymphoma cDNA library (Tipnis, 2000), and from a human cDNA library of ventricular cells with heart failure (Donoghue 2000). Expression of ACE2 has later been also identified in the heart, kidney, and testis (Donoghue et al. (2000b). However, subsequent studies have shown a much broader distribution, including the upper airways, lungs, gut, and liver (reviewed recently by Saponaro, 2020).  Tissue and  sub-cellular distribution of ACE2 (protein and mRNA) Protein expression patterns Immunostaining methods show that ACE2 is chiefly bound to cell membranes, predominantly in the smooth muscle cells and in the endothelium of the vasculature, while negligible levels can be detected in the circulation. In blood cells, it has been observed in platelets and macrophages, but not in B and T lymphocytes (Hamming et al., 2004; Fraga-Silva et al., 2011). ACE2 shows differential sub-cellular distribution which can be significant for its basal/constitutive and modulated function. It is mainly detectable at the cell-surface with little intracellular localization, and the protein does not readily internalize (Warner et al., 2005). In polarized cells, ACE2 is exclusively targeted to the apical surface in vivo in kidney (Warner 2005) and in vitro in polarised cells derived from the colon, lung and kidney (Ren 2006). This is in contrast to its sequence homologue and functional “balancer” ACE, which distributes equally between apical and basolateral surfaces (Warner 2005). In the small intestines, ACE2 is highly expressed on enterocytes and via its local RAS function participates in the regulation of the intestinal glucose transport. Intestinal ACE2 generates locally Ang 1-7 from luminal Ang II. Ang II was shown to inhibit SGLT1-dependent intestinal glucose uptake in a dose-dependent manner in vitro and in vivo in rats (Wong et al, 2007; 2009) and in human biopsies via AT1R activation (Casselbrant et al., 2015). mRNA expression patterns More recently, Qi. et al 2020 analysed 13 human tissues by scRA sequencing and report that ACE2 mRNA was mainly expressed in the ileum enterocytes, kidney proximal tubules and lung AT2 cells. ACE2 mRNA was also detected but to a lesser extent in the colon enterocytes, esophagus and keratinocytes and minimally in the cholangiocytes (biliary cells of the liver). </td> </tr> </tbody> </table>

Zunke  2017 - <a href="http://dx.doi.org/10.1016/j.bbamcr.2017.07.001">http://dx.doi.org/10.1016/j.bbamcr.2017.07.001</a> Tipnis, 2000; doi: 10.1074/jbc.M002615200 Donoghue 2000 - <a href="https://doi.org/10.1161/01.RES.87.5.e1">https://doi.org/10.1161/01.RES.87.5.e1</a> Vickers 2002 - DOI 10.1074/jbc.M200581200 Hamming 2007 – DOI: 10.1002/path.2162 Rice 2004 - DOI 10.1042/BJ20040634 Sodhi 218 - DOI 10.1042/BJ20040634 Fraga-Silva et al., 2011: 10.1590/S1807-59322011000500021 Qi. et al 2020 - doi.org/10.1016/j.bbrc.2020.03.044 Ren 2006 - DOI 10.1099/vir.0.81749-0 Warner 2005 - doi: 10.1074/jbc.M508914200 Ziegler 2020 - doi.org/10.1016/j.cell.2020.04.035 Yuan 2007 - DOI 10.1074/jbc.M705495200 Garvin et al. eLife 2020; 9:e59177. DOI: <a href="https://doi.org/10.7554/eLife.59177">https://doi.org/10.7554/eLife.59177</a> <a href="https://pubmed.ncbi.nlm.nih.gov/?term=van+de+Veerdonk+FL&cauthor_id=32338605">van de Veerdonk</a> 2020 - <a href="https://doi.org/10.7554/elife.57555">10.7554/eLife.57555</a> Nicolau et al., (2020) <a href="https://doi.org/10.1016/j.mehy.2020.109886">https://doi.org/10.1016/j.mehy.2020.109886</a> Jiqi Wang 2020 -/doi.org/10.1016/j.pharmthera.2020.107628 Ziegler, 2020 - <a href="https://doi.org/10.1016/j.cell.2020.04.035">https://doi.org/10.1016/j.cell.2020.04.035</a> Lu and Sun, 2020 - DOI 10.1074/jbc.RA120.015303 Saponaro 2020 - doi: 10.3389/fmolb.2020.588618 Glinsky 2020, unreviewed pre-print <a href="https://arxiv.org/abs/2003.13665v1">arXiv:2003.13665v1</a> Patel 2014 - dx.doi.org/10.1016/j.yjmcc.2013.11.017 Roca-Ho, 2017 - doi:10.3390/ijms18030563 Xie et al., 2006 - doi: <a href="https://dx.doi.org/10.1016%2Fj.lfs.2005.09.038">10.1016/j.lfs.2005.09.038</a> Lu and Sun, 2020 - DOI 10.1074/jbc.RA120.015303 Liu 2014 - http://dx.doi.org/10.1016/j.virusres.2014.03.010 Yang 2014 - DOI: 10.1038/srep07027 Zou 2014 - DOI: 10.1038/ncomms4594 Koka 2008 - DOI: 10.2353/ajpath.2008.070762 Glowacka 2010: doi:10.1128/JVI.01248-09 Guy 2008: 10.1113/expphysiol.2007.040139 Peng Jia 2009: 10.1152/ajplung.00071.2009 Lambert 2008: 10.1016/j.febslet.2007.11.085 Hashimoto 2012: 0.1038/nature11228 Yan 2020:  <a href="https://dx.doi.org/10.1126%2Fscience.abb2762">10.1126/science.abb2762</a> Camargo 2020: 10.1042/CS20200477 Camargo 2009: 10.1053/j.gastro.2008.10.055 Lichtenthaler 2018: 10.15252/embj.201899456 Santos 2019: 10.1152/ajpheart.00723.2018 Kakoki & Oliver, 2009: doi:10.1038/ki.2008.64 Guide to PHARMACOLOGY, accessed 21/6/21, <a href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1614">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1614</a>. Hernandes Prada et al, 2008: 10.1161/HYPERTENSIONAHA.107.108944 Bourgonje et al. (2020): <a href="https://doi.org/10.1002/path.5471">doi.org/10.1002/path.5471</a> Yang 2020 : <a href="https://doi.org/10.1161/HYPERTENSIONAHA.120.15360">doi.org/10.1161/HYPERTENSIONAHA.120.15360</a> Koester 2021: doi.org/10.1371/journal.pone.0248730 Widiasta 2020 -10.1016/j.ncrna.2020.09.001; Lu 2020 - 10.1016/j.yjmcc.2020.08.017; Fang 2017 - PMCID: PMC5376019 Lambert 2014 - 10.1042/CS20130420 AOPWiki 2021-03-31T04:33:12

2023-02-18T12:20:43

Gut microbiota, alteration

Gut dysbiosis

Organ

Gut dysbiosis features one or more of the following non-mutually exclusive characteristics 1,2: <ul> <li dir="ltr" style="list-style-type:disc"> Bloom of pathobionts (members of the commensal microbiota that have the potential to cause pathology). Such bacteria are typically present at low relative abundances but proliferate when aberrations occur in the intestinal ecosystem </li> <li dir="ltr" style="list-style-type:disc"> Loss of commensals, the reduction or complete loss of normally residing members of the microbiota, which can be the consequence of microbial killing or diminished bacterial proliferation </li> <li dir="ltr" style="list-style-type:disc"> Loss of diversity, characteristic of disease-associated dysbiosis </li> </ul>

Among the culture independent methods, nucleic acids (amplicon sequencing, WGS, metatranscriptomics), proteins (metaproteomics) and metabolites (metabolomics) based methodologies are used to obtain the taxonomical and/or the functional profiles of the gut microbiome 12. The comparative analysis between meta-data obtained from the profiling of different groups (e.g. healthy vs diseased subjects) is used to detect dysbiosis.  Comparative analysis of TAXONOMIC SIGNATURES - Gut microbiome diversity measurements include alpha diversity (among the commonly used estimators there are: Shannon index, Chao1 index, Operational Taxonomic Unit (OTU) richness, Simpson index, Faith’s Phylogenetic diversity, and Abundance-based Coverage Estimators (ACE) index); beta diversity (e.g. UniFrac, Bray-Curtis dissimilarity). To qualify the term dysbiosis, several indexes have been defined and applied (Table 1, references in the table are detailed in 13) 13. Such indexes, interpreted in the context of the clinical findings, may help to characterize diseases and adverse conditions, predict treatment outcomes, and provide information other than the commonly used alpha and beta diversity assessments. The Firmicutes/Bacteroidetes (F/B) ratio is widely accepted to have an important influence in maintaining normal intestinal homeostasis. Increased or decreased F/B ratio is used as an indicator of dysbiosis 14. However, other compositional changes at family, genus, or species level, might be more relevant than the Firmicutes/Bacteroidetes ratio. Comparative analysis of FUNCTIONAL SIGNATURES - It has been noted by several groups that function seems more highly conserved across samples than across taxa, suggesting that function is more resilient across communities than the individual strains that come and go 15. In contrast to the indexes described above, evidence of functional dysbiosis are obtained by comparing e.g. metagenomic functional compositions predicted from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database 16, proportions of Clusters of Orthologous Groups (COG) encoding proteins, functional states based on peptides and/or proteins identified by MS 17, metabolomic profiles 18.

Homo sapiens nonhuman primate model (Rhesus macaques and cynomolgus macaques)9

High Male High Female

High

All life stages

High High Moderate High References <ol> <li dir="ltr" style="list-style-type:decimal"> Hooks and O’Malley. Dysbiosis and Its Discontents. mBio 8 (2017). </li> </ol>   <ol start="2"> <li dir="ltr" style="list-style-type:decimal"> Levy, M., Kolodziejczyk, A., Thaiss, C. et al. Dysbiosis and the immune system. Nat Rev Immunol 17, 219–232 (2017). </li> </ol>   <ol start="3"> <li dir="ltr" style="list-style-type:decimal"> Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 159:944–55 e8. (2020).  </li> <li dir="ltr" style="list-style-type:decimal"> Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, et al. Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza. Clin Infect Dis. 71:2669–78 (2020).  </li> <li dir="ltr" style="list-style-type:decimal"> Petrillo M, Brogna C, Cristoni S et al. Increase of SARS-CoV-2 RNA load in faecal samples prompts for rethinking of SARS-CoV-2 biology and COVID-19 epidemiology. F1000Research, 10:370 (2021). </li> <li dir="ltr" style="list-style-type:decimal"> Gubernatorova EO, Gorshkova EA, Polinova AI, Drutskaya MS. IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 53:13–24 (2020). </li> <li dir="ltr" style="list-style-type:decimal"> Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 70:698–706 (2021).  </li> <li dir="ltr" style="list-style-type:decimal"> Forslund, S.K., Chakaroun, R., Zimmermann-Kogadeeva, M. et al. Combinatorial, additive and dose-dependent drug–microbiome associations. Nature (2021). </li> <li dir="ltr" style="list-style-type:decimal"> Sokol H, Contreras V, Maisonnasse P,  et al. SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota. Gut Microbes.  13(1):1-19 (2021). </li> <li dir="ltr" style="list-style-type:decimal"> Saraswati S and Sitaraman R. Aging and the human gut microbiota—from correlation to causality. Front. Microbiol. 5:764 (2015).  </li> <li dir="ltr" style="list-style-type:decimal">  O’Toole P W  and Jeffery I B. Gut microbiota and aging. Science 350, 1214-1215 (2015) </li> <li dir="ltr" style="list-style-type:decimal"> Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 70 Suppl 1(Suppl 1):S38-S44. (2012). </li> <li dir="ltr" style="list-style-type:decimal"> Wei S, Bahl MI, Baunwall SMD, Hvas CL, Licht TR. Determining Gut Microbial Dysbiosis: a Review of Applied Indexes for Assessment of Intestinal Microbiota Imbalances. Appl Environ Microbiol.  87(11):e00395-21. (2021). </li> <li dir="ltr" style="list-style-type:decimal"> Stojanov, S.; Berlec, A.; &Scaron;trukelj, B. The Influence of Probiotics on the Firmicutes/Bacteroidetes Ratio in the Treatment of Obesity and Inflammatory Bowel disease. Microorganisms 8, 1715. (2020).  </li> <li dir="ltr" style="list-style-type:decimal"> Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486:207–214. (2012).  </li> <li dir="ltr" style="list-style-type:decimal"> Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol 21(3):803-814 (2015). </li> <li dir="ltr" style="list-style-type:decimal"> Sajulga R, Easterly C, Riffle M, Mesuere B, Muth T, Mehta S, et al. Survey of metaproteomics software tools for functional microbiome analysis. PLoS ONE 15(11): e0241503. (2020). </li> <li dir="ltr" style="list-style-type:decimal"> Peter E. Larsen, Yang Dai, Metabolome of human gut microbiome is predictive of host dysbiosis, GigaScience, 4, s13742–015–0084–3. (2015). </li> </ol> AOPWiki 2021-11-30T07:02:49

2022-01-04T10:31:44

<upstream-id>233c58b1-8a39-47ea-9803-9792628ede5d</upstream-id> <downstream-id>89eeaa3b-a5a7-43c2-b10c-8d19e8e4d472</downstream-id> 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.

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).

<table cellspacing="0" class="Table" style="border-collapse:collapse; width:962px"> <tbody> <tr> <td style="background-color:#262626; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:137px"> Aspect of ACE2 dysregulation after S-binding </td> <td style="background-color:#262626; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:208px"> WoE </td> <td style="background-color:#262626; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:430px"> Rationale </td> <td style="background-color:#262626; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:186px"> Empirical evidence Ref. </td> </tr> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:137px"> Molecular level view ACE2 enzymatic function is dysregulated </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Moderate ↑ </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:430px"> 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. </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:186px"> 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]   </td> </tr> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:137px"> Cellular/Tissue-Plasma level view ACE2 protein level is dysregulated </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> High   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 </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:430px"> 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. </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:186px"> 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 </td> </tr> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:137px"> Cellular level view Ace2 mRNA level is dysregulated </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Moderate   ↓ ? ↑ </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:430px"> 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). </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:186px"> 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] </td> </tr> </tbody> </table>

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.

This KER summarises the evidence for dysregulation of ACE2 (KE 1854) as a result of binding of the viral spike (S) protein of SARS-COV and SARS-COV2 (KE1739). This is likely an important aspect of COVID19 pathogenesis as an initial step it is a potential target for intervention at (re)infection but also for treatment of the disease. In addition, it is important to summarise the exiting evidence for this KER as the majority of hypotheses on the pathogenesis of COVID19 and potential treatments consider S protein binding leads to down-regulation of ACE2. The evidence included in this KER was identified in the period between October 2020 and March 2021 with a Pubmed search syntax……, and additional targeted searches for specific aspects to ACE2 regulation. The searches were aimed to identify the evidence for the effect of SARS-COV or SARS-COV2 on any aspect ofACE2 regulation i.e. effect on expression of ACE2 at mRNA or protein level, ACE2 shedding and enzymatic activity, all described in KE 1854. The studies generally use SARS-COV or SARS-COV2 Virus like Particles (pseudovirus), recombinant or transiently expressed S protein from SARS-COV and SARS-COV2 (in Table 1 designated S protein (1) and S-protein (2), respectively) in various cell lines e.g. Vero E6 and Huh7-that express endogenous ACE2 or HEK293T transfected with ACE2 expressing vectors. Concurrent increase of the soluble form of ACE2 (sACE2) and/or enzymatic (peptidase) activity is monitored in some of the studies (Table). The evidence mostly relates to evaluation of direct binding of S protein to ACE2, but some evidence is indirect and can potentially relate to dysregulation resulting from infection progression/viral replication and reinfection of new cells in the context of the parallel inflammatory processes. Details of the evidence for dysregulation of ACE2 at mRNA and protein level (including enzymatic activity) as a result of interaction with SARS-COV 1 and 2 S proteins:  : <a href="https://aopwiki.org/system/dragonfly/production/2022/02/12/8oiauj0w7m_Empirical_evidence_ACE2_dysregulation_120222.pdf" style="color:blue; text-decoration:underline">https://aopwiki.org/system/dragonfly/production/2022/02/12/8oiauj0w7m_Empirical_evidence_ACE2_dysregulation_120222.pdf</a> GI tract specific evidence for dysregulation at mRNA level <table cellspacing="0" class="Table" style="border-collapse:collapse; width:950px"> <tbody> <tr> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:81px"> Stressor </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:66px"> "dose" </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:94px"> ACE2 mesuement </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:85px"> dysregultion type </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:47px"> time point </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:94px"> test system </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:113px"> tissue </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:66px"> species </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:95px"> note </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:76px"> note2 </td> <td style="background-color:#d9d9d9; height:83px; vertical-align:top; width:132px"> ref </td> </tr> <tr> <td style="background-color:#fde9d9; height:41px; width:81px"> SARS-COV2 </td> <td style="background-color:#fde9d9; height:41px; width:66px"> 1 MOI </td> <td style="background-color:#fde9d9; height:41px; width:94px"> protein - cell lysate </td> <td style="background-color:#fde9d9; height:41px; width:85px"> up </td> <td style="background-color:#fde9d9; height:41px; width:47px"> 72hpi </td> <td style="background-color:#fde9d9; height:41px; width:94px"> cell ine </td> <td style="background-color:#fde9d9; height:41px; width:113px"> GI - colorectal adenocarcinoma </td> <td style="background-color:#fde9d9; height:41px; width:66px"> human </td> <td style="background-color:#fde9d9; height:41px; width:95px">   </td> <td style="background-color:#fde9d9; height:41px; width:76px">   </td> <td rowspan="2" style="background-color:#fde9d9; height:41px; width:132px"> Lee at all (2020) 10.1080/22221751.2020.1827985 </td> </tr> <tr> <td style="background-color:#fde9d9; height:41px; width:81px"> SARS-COV2 </td> <td style="background-color:#fde9d9; height:41px; width:66px"> 1 MOI </td> <td style="background-color:#fde9d9; height:41px; width:94px"> mRNA -qRT-PCR </td> <td style="background-color:#fde9d9; height:41px; width:85px"> up </td> <td style="background-color:#fde9d9; height:41px; width:47px"> 72hpi </td> <td style="background-color:#fde9d9; height:41px; width:94px"> cell ine </td> <td style="background-color:#fde9d9; height:41px; width:113px"> GI - colorectal adenocarcinoma </td> <td style="background-color:#fde9d9; height:41px; width:66px"> human </td> <td style="background-color:#fde9d9; height:41px; width:95px">   </td> <td style="background-color:#fde9d9; height:41px; width:76px">   </td> </tr> <tr> <td style="background-color:#daeef3; height:23px; width:81px"> SARS-COV2 </td> <td style="background-color:#daeef3; height:23px; width:66px"> 1 MOI </td> <td style="background-color:#daeef3; height:23px; width:94px"> mRNA - qRT-PCR </td> <td style="background-color:#daeef3; height:23px; width:85px"> up </td> <td style="background-color:#daeef3; height:23px; width:47px"> 48hpi </td> <td style="background-color:#daeef3; height:23px; width:94px"> organoid -3D </td> <td style="background-color:#daeef3; height:23px; width:113px"> GI - colon </td> <td style="background-color:#daeef3; height:23px; width:66px"> human </td> <td style="background-color:#daeef3; height:23px; width:95px">   </td> <td style="background-color:#daeef3; height:23px; width:76px">   </td> <td rowspan="2" style="background-color:#daeef3; height:23px; width:132px"> Heuberger et al., 2021 10.15252/emmm.202013191 </td> </tr> <tr> <td style="background-color:#daeef3; height:32px; width:81px"> SARS-COV2 </td> <td style="background-color:#daeef3; height:32px; width:66px"> 1 MOI </td> <td style="background-color:#daeef3; height:32px; width:94px"> mRNA - bulk transcriptomics </td> <td style="background-color:#daeef3; height:32px; width:85px"> up </td> <td style="background-color:#daeef3; height:32px; width:47px"> 48hpi </td> <td style="background-color:#daeef3; height:32px; width:94px"> organoid -3D </td> <td style="background-color:#daeef3; height:32px; width:113px"> GI - colon </td> <td style="background-color:#daeef3; height:32px; width:66px"> human </td> <td style="background-color:#daeef3; height:32px; width:95px">   </td> <td style="background-color:#daeef3; height:32px; width:76px">   </td> </tr> <tr> <td style="background-color:#ebf1de; height:41px; width:81px"> SARS-COV2 </td> <td style="background-color:#ebf1de; height:41px; width:66px"> 1 MOI </td> <td style="background-color:#ebf1de; height:41px; width:94px"> mRNA - bulk RNAsec </td> <td style="background-color:#ebf1de; height:41px; width:85px"> up* </td> <td style="background-color:#ebf1de; height:41px; width:47px"> 60hpi </td> <td style="background-color:#ebf1de; height:41px; width:94px"> organoid -3D </td> <td style="background-color:#ebf1de; height:41px; width:113px"> GI- illeum </td> <td style="background-color:#ebf1de; height:41px; width:66px"> human </td> <td style="background-color:#ebf1de; height:41px; width:95px"> *modest? (24h not disscussed. See Nataf & Pays (2021) </td> <td style="background-color:#ebf1de; height:41px; width:76px"> in DIF organoids </td> <td rowspan="2" style="background-color:#ebf1de; height:41px; width:132px"> Lamers et al., 2020 10.1126/science.abc1669 </td> </tr> <tr> <td style="background-color:#ebf1de; height:23px; width:81px"> SARS-COV1 </td> <td style="background-color:#ebf1de; height:23px; width:66px"> 1 MOI </td> <td style="background-color:#ebf1de; height:23px; width:94px"> mRNA - bulk RNAsec </td> <td style="background-color:#ebf1de; height:23px; width:85px"> up* </td> <td style="background-color:#ebf1de; height:23px; width:47px"> 24hpi 60hpi </td> <td style="background-color:#ebf1de; height:23px; width:94px"> organoid -3D </td> <td style="background-color:#ebf1de; height:23px; width:113px"> GI- illeum </td> <td style="background-color:#ebf1de; height:23px; width:66px"> human </td> <td style="background-color:#ebf1de; height:23px; width:95px"> *modest? </td> <td style="background-color:#ebf1de; height:23px; width:76px"> in EXP organoids </td> </tr> <tr> <td style="height:97px; width:81px"> SARS-COV2 </td> <td style="height:97px; width:66px"> 1 MOI </td> <td style="height:97px; width:94px"> mRNA - bulk RNAsec </td> <td style="height:97px; width:85px"> down </td> <td style="height:97px; width:47px"> 24hpi </td> <td style="height:97px; width:94px"> organoid -3D </td> <td style="height:97px; width:113px"> GI- illeum </td> <td style="height:97px; width:66px"> human </td> <td style="height:97px; width:95px"> re-analysed data by Lamers et al., 2020 </td> <td style="height:97px; width:76px"> Concomitant down-reg of B0AT transporter. But note all genes that they looked at were down at 24 and recovered by 60hpi. </td> <td style="height:97px; width:132px"> Nataf & Pays (2021) [10.3390/ijms221910440 </td> </tr> <tr> <td style="background-color:#e4dfec; height:60px; width:81px"> SARS-COV2 </td> <td style="background-color:#e4dfec; height:60px; width:66px"> 1000K pfu </td> <td style="background-color:#e4dfec; height:60px; width:94px"> mRNA - scRNAseq </td> <td style="background-color:#e4dfec; height:60px; width:85px"> down </td> <td style="background-color:#e4dfec; height:60px; width:47px"> 12hpi 24hpi </td> <td style="background-color:#e4dfec; height:60px; width:94px"> organoid -2D </td> <td style="background-color:#e4dfec; height:60px; width:113px"> GI - illeum </td> <td style="background-color:#e4dfec; height:60px; width:66px"> human </td> <td style="background-color:#e4dfec; height:60px; width:95px"> down-reg effect in both infected and bystanders compared to mock </td> <td style="background-color:#e4dfec; height:60px; width:76px">   </td> <td rowspan="2" style="background-color:#e4dfec; height:60px; width:132px"> Triana et al., (2021) [10.15252/msb.202110232] </td> </tr> <tr> <td style="background-color:#e4dfec; height:69px; width:81px"> SARS-COV2 </td> <td style="background-color:#e4dfec; height:69px; width:66px"> 1000K pfu </td> <td style="background-color:#e4dfec; height:69px; width:94px"> mRNA - scRNAseq </td> <td style="background-color:#e4dfec; height:69px; width:85px"> down </td> <td style="background-color:#e4dfec; height:69px; width:47px"> 12hpi 24hpi </td> <td style="background-color:#e4dfec; height:69px; width:94px"> organoid -2D </td> <td style="background-color:#e4dfec; height:69px; width:113px"> GI - colon </td> <td style="background-color:#e4dfec; height:69px; width:66px"> human </td> <td style="background-color:#e4dfec; height:69px; width:95px"> down-reg effect only in infected cells, no effect in bystanders compared to mock </td> <td style="background-color:#e4dfec; height:69px; width:76px">   </td> </tr> </tbody> </table>

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 <a href="https://doi.org/10.3390/jcm11185400">https://doi.org/10.3390/jcm11185400</a>) 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.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> <tr> <th> </th> <th> </th> <th> </th> <th> </th> </tr> </thead> <tbody> <tr> <td> Sex </td> <td> both male and female sex (XX and XY chromosomes) </td> <td> 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. </td> <td> 1. doi: 10.1177/1933719115597760 2. doi: 10.3390/ijms21082948 3. doi: 10.1038/nature03712 4. doi: 10.1038/nm1267 </td> </tr> <tr> <td> Chemicals (weak evidence) </td> <td> PFAS (PFOA) </td> <td> One study showed that PFOA upregulates ACE2 expression in lungs [1]. </td> <td> 1. doi: <a href="https://doi.org/10.1016/j.toxrep.2021.11.014" rel="noreferrer noopener" target="_blank" title="Persistent link using digital object identifier">10.1016/j.toxrep.2021.11.014</a> </td> </tr> <tr> <td> Vitamin D moderate evidence) </td> <td> Vit D deficiency </td> <td> 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]. </td> <td> 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 </td> </tr> <tr> <td> Genetic factors </td> <td>   </td> <td> 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. </td> <td> 1. doi: 10.1097/FPC.0000000000000436 </td> </tr> <tr> <td> Pre-existing heart failure </td> <td> </td> <td> 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]. </td> <td> 1: https://doi.org/10.1016/j.cbi.2021.109738  2: https://doi.org/10.1042/CS20210735 </td> </tr> <tr> <td>Diet</td> <td>Several dietary compounds impact the ACE axis</td> <td> 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]. </td> <td> <ul> <li>206: <a href="http://doi.org/10.1007/s11010-021-04275-2">http://doi.org/10.1007/s11010-021-04275-2</a></li> <li>215: <a href="http://doi.org/10.1093/nutrit/nuaa126">http://doi.org/10.1093/nutrit/nuaa126</a></li> <li>216: <a href="http://doi.org/10.1080/21623945.2021.1965315">http://doi.org/10.1080/21623945.2021.1965315</a></li> </ul> </td> </tr> </tbody> </table>   </div>

AOPWiki 2021-03-31T04:39:33

2023-02-07T23:35:22

<upstream-id>89eeaa3b-a5a7-43c2-b10c-8d19e8e4d472</upstream-id> <downstream-id>9fe03a8f-c6b8-452a-a7ab-db49f36845fd</downstream-id>

AOPWiki 2021-12-02T07:16:44

2021-12-02T07:16:44

Binding of S-protein to ACE2 in enterocytes induces ACE2 dysregulation leading to gut dysbiosis

ACE2 dysregulation leads to gut dysbiosis

Laure-Alix Clerbaux

Laure-Alix Clerbaux, Julija Filipovska, Amalia Munoz-Pineiro, Lucia Grenga Cinzia La Rocca

BY-SA

Under Development

1.96

2.0

S-protein binding to <a href="https://bioregistry.io/genecards:ACE2">ACE2</a> receptor induces dysregulation of <a href="https://bioregistry.io/genecards:ACE2"> ACE2</a> physiological functions in the intestines such as modulation of the local renin-angiotensin signaling (<a href="http://amigo.geneontology.org/amigo/term/UBERON:0018229">RAS</a>) system (<a href="http://doi.org/10.1152/ajpgi.00099.202">10.1152/ajpgi.00099.202</a>) or as a chaperone for dietary amino acid (AA) transporters in the intestines, such as the tryptophan transporter <a href="https://www.genecards.org/Search/Keyword?queryString=B0AT1%20">B0AT1 </a>(Slc6a19) (<a href="http://doi.org/10.1042/CS20200477">10.1042/CS20200477</a>; <a href="http://doi.org/10.1053/j.gastro.2008.10.055">10.1053/j.gastro.2008.10.055</a>). The gastrointestinal <a href="http://amigo.geneontology.org/amigo/term/UBERON:0018229">RAS </a>appears to be involved in numerous processes in the gut including AA, fluid and electrolyte absorption and secretion (<a href="https://doi.org/10.1111/j.1365-2036.2011.04971.x">10.1111/j.1365-2036.2011.04971.x.</a>). Besides, the gut microbiota is influenced by the host intestinal AA metabolism as gut bacteria use dietary AA for protein synthesis (<a href="https://doi.org/10.1038/s41598-020-74122-9">10.1038/s41598-020-74122-9</a>). AOP428 has been developed within the <a href="https://www.ciao-covid.net/">CIAO project</a> - "Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP)". The overall goal is to organize the vast amount of data that is constantly evolving as a result of the COVID-19 pandemic and identify uncertainties and knowledge gaps that may be missing using the AOP framework. Many AOPs were developed in the CIAO project, each AOP focusing on a specific element of the SARS-COV-2 virus responses in humans. AOP428 focuses on the alteration of the gut microbiota via <a href="https://bioregistry.io/genecards:ACE2">ACE2 </a>dysregulation in the gut.

Receptor recognition is an essential determinant of molecular level in this AOP. ACE2 was reported as an entry receptor for SARS-CoV-2. The viral entry process is mediated by the envelope-embedded surface-located spike (S) glycoprotein.  Jun Lan and Walls, A.C et al (Nature 581, 215–220; Cell 180, 281–292) demonstrated a critical initial step of infection at the molecular level from the interaction of ACE2 and S protein. ACE2 has shown that receptor binding affinity to S protein is nM range. To elucidate the interaction between the SARS-CoV-2 RBD and ACE2 at a higher resolution, they also determined the structure of the SARS-CoV-2 RBD–ACE2 complex using X-ray crystallography. The expression and distribution of the ACE2 in human body may indicate the potential infection of SARS-CoV-2. Through the developed single-cell RNA sequencing (scRNA-Seq) technique and single-cell transcriptomes based on the public database, researchers analyzed the ACE2 RNA expression profile at single-cell resolution. High ACE2 expression was identified in type II alveolar cells (Zou, X. et al. Front. Med.2020) SARS-CoV-2 belongs to the Coronaviridae family, which includes evolutionary related enveloped (+) strand RNA viruses of vertebrates, such as seasonal common coronaviruses, SARS-CoV and CoV-NL63, SARS-CoV (Kim Young Jun et al) <table cellspacing="0" class="Table" style="border-collapse:collapse; width:1248px"> <tbody> <tr> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:206px"> Human viruses strains </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Genus </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Major cell receptor </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> First report </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Animal reservoir </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:204px"> Intermediate host </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:340px"> Pathology </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:252px"> Diagnostic test </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:182px"> Evidence </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> HCoV-NL63 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Alphacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2004 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Unknown </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Mild respiratory tract illness </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> SARS-CoV </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Betacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2003 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Pangolin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Severe acute respiratory syndrome </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> SARS-CoV-2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Betacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2020 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Pangolin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Severe acute respiratory syndrome </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> </tbody> </table>

adjacent

Not Specified

Moderate adjacent

Moderate

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

AOPWiki 2021-10-19T13:52:33

2023-04-29T16:03:05