The Controversy on the Role of ACE2 Receptor in COVID-19 Infection: The Protective Shift toward the ACE2 Axis

Background: Angiotensin-converting enzyme 2 (ACE2) is recognized as the main cellular receptor for the new coronavirus, SARS-CoV-2, that facilitates its entry into the host target cell, leading to the fatal viral infection, coronavirus disease 2019 (COVID-19). Thus, it is considered as a main therapeutic target in the SARS-CoV-2 infection. The dual role of ACE2 as a gate for SARS-CoV-2 virus and as a part of lung and multi-organ protection has built a scientific debate that affects the choice of treatments used against COVID-19 patient. ACE2 inhibitors like anti-ACE2 antibodies were first introduced as therapeutic solutions that, theoretically, would decrease the availability of target molecules for SARS-CoV-2 by downregulating ACE2 expression. However, animal studies showed that ACE2 upregulation acts as a counterbalance to the hypertensive pro-inflammatory angiotensin I-converting enzyme (ACE) in the renin-angiotensin system (RAS) and results in a protective role against acute lung injury - a fatal consequence of the disease. The current study tests the effect of ACE2-activating treatments against the outcome of genetic variations in the population that have ACE2-upregulatory effects. Conclusion Despite its role as a receptor for the SARS-CoV-2 virus, experimental studies and the genetic polymorphisms in populations that have ACE2 upregulation revealed a protective role against COVID-19 infection.