Current studies show that many organs that are heavily affected by COVID-19 have a high expression level of ACE2.

- Cardiovascular system
- Central nervous system (CNS)
- Gastrointestinal tract (GI)
- Kidney
- Liver 
- Lungs (Respiratory System)
- Peripheral nervous system (PNS)
- Testis

Organs and Organ Systems Affected by COVID-19

A majority of the COVID-19 symptoms are due to high or low ACE2 expression. Only 1 symptom can be seen when ACE2 protein expression is in the middle.

Tissue ACE2 Expression Levels as Related to COVID-19 Symptoms

- Inflammation of endothelial cells in the heart, lung, and small bowel
- A COVID-19 patient's kidneys were unable to filter blood and necrosis was present in the small intestine
- Another COVID-19 patient was found to have inflammation in the endothelial layer of the small intestine
- ACE2 receptors are used by the COVID-19 virus in the epithelial alveolar lining of the lungs, resulting in lung damage
- ACE2 receptors are located on endothelial cells, which are located in other organs and can negatively impact them
- Image shows an excess of mononuclear cells in the lung, resulting in the blockage of the small vessels in the lung


Effects of the ACE2 receptors on organ tissues of COVID-19 patients

Expression levels were determined using the HPA (https://www.proteinatlas.org).  Tissues that express ACE2 were broken down into five categories based off of the amount of ACE2 mRNA expression:

- (1, highest expression, score range: 122-10) small intestine, colon, duodenum, kidney, testis, gallbladder and heart muscle
- (2, medium high expression, score range: 5-1) adipose tissue, thyroid gland, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland and placenta
- (3, medium low expression, score range: 0.9-0.5) vagina, lung, appendix, skeletal muscle, fallopian tube, lymph node, tongue, stomach and prostate
- (4, low expression, score range: 0.4-0.1) remaining tissues
- (5, no expression, score range: 0) parathyroid gland, bone marrow, monocytes, B-cells, NK-cells, dendritic cells and total peripheral blood mononuclear cell

ACE2 Protein and mRNA Expression in Tissue

- increased ACE2 expression as a risk factor for COVID-19
- decreased ACE2 activity in comorbidities as a risk factor for COVID-19 symptom severity
- inconsistencies in ACE2 expression hypotheses

Hypotheses Regarding ACE2 Expression in Tissue and COVID-19

The HCCDB gene expression database (http://lifeome.net/database/hccdb/home.html) was used to determine ACE2 expression levels in both human adipose and lung tissue.  

- ACE2 gene expression was higher in both subcutaneous and visceral adipose tissue compared to lung tissue
- previous studies have shown that obesity alone does not affect ACE2 expression, but this study shows that obese individuals with more adipose tissue will consequently have more ACE2 receptors
- this study does not prove that SARS-CoV-2 can infect human adipose tissue or propose a possible mechanism of infection

ACE2 Expression in Adipose Tissue May Contribute to COVID-19 Morbidity and Mortality in Obese Patients

This graph displays the variance in the amount of ACE2 expression there is different types of tissues within the human body. 

Graph of the Expression of ACE2 in Various Tissues

ACE2 is known to be expressed in a variety of different tissues, including:

- Heart, kidneys, gastrointestinal (GI) tract, lungs, brain, testes, bladder, adipose tissue, vascular system, cholangiocytes (epithelial cells of the oral and nasal mucosa)

ACE2 expression may explain the SARS-CoV-2 organ localization.

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Three primary observations have been made about ACE2 and its relation to SARS/COVID-19:

- ACE2 acts as a functional receptor for SARS-CoV-2 to enter host cells
- Increased ACE2 expression may elevate the risk of a SARS-CoV-2 infection as well as the development of COVID-19
- Reduced ACE2 expression may lead to acute respiratory distress syndrome

SARS‐CoV‐2 may be able to infect other tissues that express ACE2 using viral RNA that circulates in the blood.  

ACE2 in the Pathogenesis of COVID-19

ACE2 is expressed throughout many human tissues and organs. This node organizes the tissue- and organ-level expression findings for ACE2, covering: expression in cancer tissue; expression in the human airway epithelium; expression in the human brain; ACE2 protein and mRNA expression levels across tissues; and the relationship between tissue ACE2 expression and COVID-19.

ACE2 Expression in Tissue and Organs

Tan, H. W., Xu, Y. M., & Lau, A. T. Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection. Reviews in Medical Virology, e2122. https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2122

Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection

Klhůfek, J. (2020). The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero?. Acta Clinica Belgica, 1-8. https://www.tandfonline.com/doi/full/10.1080/17843286.2020.1786324
doi: 10.1080/17843286.2020.1786324

The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero?

SARS-CoV-2 relies on its spike (S) protein to bind to cellular receptors to enter host cells. SARS-S, the SARS spike protein, uses ACE2 as an entry receptor into cells. Then the virus utilizes the serine protease TMPRSS2 found within the cell to enhance entry and prime future S proteins. SARS‐CoV‐2 is thought to be more transmissible than others CoVs because its S proteins have a greater affinity for ACE2.

ACE2 as a Receptor for SARS-CoV-2

Expression of ACE2 in Tissue and COVID-19

Some believe that the body may initiate an autoimmune response when SARS-CoV-2 is attached to an ACE2 receptor.  The body may consider this complex antigenic, meaning it produces antibodies.  However, these antibodies would target both the virus and ACE2.  This theory is substantiated by:

- the patterns of lung damage in patients with Pulmonary Hypertension secondary to Scleroderma, which is hallmarked by high levels of anti-ACE2 antibodies
- the severity of COVID-19 immune responses in those with cardiovascular disease and hypertension, who would be likely to have increased levels of ACE2 receptors in their blood serum

Measuring ACE2 levels in serum could be a way of predicting at-risk groups for ARDS (acute respiratory distress syndrome) and other hyperimmune responses.  

Autoimmunity to ACE2 Theory in the Pathogenesis of COVID-19

COVID-19 results in the down-regulation of ACE2 receptors by the virus binding to transcription factors at ACE2 regulatory regions on the gene.  This results in increased concentrations of Ang II, which would normally be converted to Ang 1-7 by ACE2.  This may contribute to the hyper-inflammation seen in COVID-19 patients.  

SARS-CoV-2 Down-Regulates ACE2 Receptors

- Increased Concentrations of Circulating ACE2 is Associated with Mild COVID-19 Symptoms 
- Circulating ACE2 expression compared to circulating ACE

Expression of Circulating ACE2 and COVID-19

The expression of angiotensin-converting enzyme 2 (ACE2) in various structures of the central nervous system (CNS), including neurons, neuroglial cells, and the blood-brain barrier (BBB), provides potential pathways for SARS-CoV-2 neuroinvasion. Because the virus uses the ACE2 receptor to enter host cells, the presence of ACE2 in these tissues increases the risk of direct infection and subsequent neurological complications.

ACE2 and its Implications in SARS-CoV-2 Infection of the CNS

One of the primary manifestations of COVID-19 is respiratory disease.  ACE2 expression was assessed in human airway epithelial tissue to better understand how SARS-CoV-2 interacts. with these cells. Studies included:

- ACE2 expression in healthy nonsmokers
- ACE2 expression in smokers
- ACE2 expression modulation by air pollution
- ACE2 expression modulated by miRNA (miR-1246)
- ACE2 expression in basal cells from the large and small airway epithelia of healthy nonsmokers

ACE2 Expression in Human Airway Epithelial Tissue

According to the GEPIA dataset, nearly all cancer tissues can express ACE2 with renal cancer having the highest expression level.  Some cancerous tissues were found to have a significant increase in ACE2 when compared against the same noncancerous tissue.  

Cancer Tissue Expression of ACE2

ACE2 expression was quantified in 21 regions of the human brain using multiple tissue expression (MTE) arrays (*p < 0.01 (ANOVA); error bars represent one standard deviation of the mean).  The highest expression was found in the pons, amygdala, and the medulla oblongata.  The pons and medulla oblongata are notably known to control breathing and respiration. 

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