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.  

Michigan State University

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

McLachlan, C. S. (2020). The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms. Clinical Hypertension, 26(1), 1-3.
https://clinicalhypertension.biomedcentral.com/articles/10.1186/s40885-020-00147-x

The angiotensin-converting enzyme 2
(ACE2) receptor in the prevention and
treatment of COVID-19 are distinctly
different paradigms

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

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

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

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