This finding suggests that circulating ACE2 has a protective effect.  This may be caused by SARS-CoV-2 having more targets to try and infect.  Ultimately, this would decrease the interactions the virus would have with actual tissues that express ACE .  Women and children have also been found to have greater amounts of circulating ACE2 in their blood, and this may explain why they tend to fare better with COVID-19.

Increased Concentrations of Circulating ACE2 is Associated with Mild COVID-19 Symptoms

- circulating ACE2 was 100-fold lower than circulating ACE and only detected in 40 among 534 test subjects
- indicative of less shedding of ACE2 than ACE
- most healthy individuals have little to no circulating ACE2

Circulating ACE2 expression compared to circulating ACE

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

Michigan State University

State University of New York at Stony Brook

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

- subcellular expression
- tissue and organ expression
- mediators that influence expression
- comparing to TMPRSS2 expression
- circulating expression
- expression in embryonic development

ACE2 Expression

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

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

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

- 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

Expression of Circulating ACE2 and COVID-19

Data from primary manuscripts and microscopy screenings were used to assign a confidence level to the likelihood of different subcellular locations expressing ACE2.  This study showed that the extracellular space and plasma membrane are the most likely places to express ACE2 (confidence = 5), and the Golgi apparatus is the least likely (confidence = 1) out of these listed locations.  

Subcellular Expression of ACE2

- drug mediators
- non-drug mediators
- genetic mediators
- disease states

Mediators that Infleunce ACE2 Expression

- comparing expression levels in different tissues
- comparing expression levels by sex
- coexpression of TMPRSS2 and ACE2 

Comparing TMPRSS2 and ACE2 Expression

Pregnant mice were used to assess the expression levels of the following genes associated with SARS-CoV-2, inflammation, and other viral diseases:

- ACE2: cellular receptor for the SARS-CoV-2 virus
- TMPRSS2: serine protease involved in cellular entry of the SARS-CoV-2 virus
- St3gal4: related to the influenza virus
- St6gal1: related to the influenza virus
- Ifngr1: related to inflammation
- Tnfrsf1a: related to inflammation

Mice were sacrificed at the following timepoints:

- E12.5: embryonic day 12 (gravid females are sacrificed)
- E14.5: embryonic day 14 (gravid females are sacrificed)
- P1: day pups are born (pups are sacrificed)

Epithelium (Epi) and mesenchyme (Mes) tissue were collected from the soft pallets (SP) and tongues (T) of the different developmental stages.  Notably, ACE2 expression was only observed in large quantities in P1 mice, and TMPRSS2 expression increased throughout the developmental process.  FPKM: fragments per kilobase million reads

ACE2 and Other SARS-CoV-2 Related Gene Expression in Mouse Development

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

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