- Neuronal ACE2 Expression as a Risk Factor for COVID-19
- Neuronal ACE2 Internalization in COVID-19
- ACE2 Expression in BBB
- ACE2 Expression in neuroglial cells
- ACE2 Expression in the ENS and Choroid Plexas

ACE2 and its Implications in SARS-CoV2 infection of the CNS

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. 

Michigan State University

- cancer tissue
- human airway epithelium tissue
- human brain expression
- protein and mRNA expression
- relationship to COVID-19

ACE2 Expression in Tissue and Organs

- Anosmia has been recognized as early symptoms of COVID-19 in most patients.
     - may indicate that SARS-CoV-2 has a high affinity for olfactory epithelium and 
       can utilize the olfactory nerve to enter the CNS.
          - based on the fact that the Influenza virus and other SARS viruses utilize 
             this short-cut to enter the brain. 
          - early CNS symptoms include headaches, nausea, and vomiting in patients 
               - this further points to the idea that COVID is confined to the 
                  respiratory system and the CNS.
- SARS-CoV has been observed in animal brain tissue that has been infected with heavy viral load.
- Viral invasion to CNS:
     - Prior research has shown that the olfactory nerve is a shortcut for SARS-CoV-2 
        and that there are specific SARS-CoV-2, ACE2, receptors that are abundant in 
        the brain, which helps bind viral particles.
     - Extensive neuronal infections have been reported as the main cause of death in 
        some patients when they had a minor lung infection.


Pathophysiology of the COVID-19 – entry to the CNS through the nose

Lukiw, W. J., Pogue, A., & Hill, J. M. (2020). SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cellular and Molecular Neurobiology, 1-8.
https://link.springer.com/article/10.1007/s10571-020-00947-7
doi: 10.1007/s10571-020-00947-7

SARS-CoV-2 Infectivity and Neurological Targets in the Brain

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

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

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

ACE2 Expression in the Human Brain

- Dysfunction of the Central automimic network:
     - Once the virus enters the CNS through the olfactory nerve, it can cause 
        inflammation and imbalance in brain structures that regulate the ANS. 
          - Since the parasympathetic nervous system regulates the respiration rate, 
            this can cause distress.
     - Some hospitalized patients presented with asymptomatic hypoxia with central 
        apnea, which further suggests the virus entry through the nose.
     - Several clinical and radiology studies of hospitalized patients, >1000 COVID-19 
        patients, have shown normal chest x-rays and scans despite having a severe 
        illness. 
     - Early dyspnea and hypoxia are due to central dysfunctions.

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