Increased, ectopic expression of human ACE2 in transgenic mice has been shown to correlate with an increase in SARS-CoV replication, coupled with an increase in expression of the genes furthering viral reproduction. It is hypothesized that ACE2 expression may aid viral entry and/or replication, and pose as a risk factor for COVID-19 infection/severity.

- ACE2 and viral entry: low ACE2 Expression as sufficient for SARS-CoV-2 Infection
- ACE2 and comorbidities: increased ACE2 expression in cancerous tissues


Increased ACE2 Expression as a Risk Factor for COVID-19

To date, the data surrounding ACE2 activity in COVID-19 comorbidities as a risk factor for COVID-19 severity is conflicting. The list below summarizes research findings. 

Humans:
- increased or no difference in ACE2 mRNA and proteins ~ patients with heart failure 
- decreased ACE2 activity ~ patients with diabetes mellitus
- decreased or no difference in renal ACE2 expression ~ patients with diabetic nephropathy

Animal models:
- decreased vascular ACE2 activity ~ cardiac pathogenesis

As such, the evidence surrounding the (comorbidity ACE2 expression ~ COVID-19 severity) hypothesis is lacking.

Decreased ACE2 Activity as a Risk Factor for the Severity of COVID-19

- not all cells that express ACE2 receptors get infected with SARS-CoV-2
- club cells are a prime example of cells that express both ACE2 and TMPRSS2, which are both key factors for facilitating the entry of SARS-CoV-2 yet club cells are not able to get infected
- the possible explanation for this behavior is the expression of high levels of antiviral IFN-stimulated genes
- furthermore, different expression levels of ACE2 among individuals is not also a definite predictor of disease outcome as children show similar seroprevalence rates, yet it is known that children are less vulnerable to SARS-CoV-2
- it is important to study the various other factors that facilitate entry of the virus that can account for some of the inconsistencies among literature

Inconsistencies in ACE2 Expression Hypotheses

- 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

Smith College

Michigan State University

State University of New York at Stony Brook

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.

Expression of ACE2 in Tissue and COVID-19

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

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. 

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