The Angiotensin-Converting Enzyme 2 (ACE2) receptor is a protein found on the surface of human cells that acts as the main cellular entry point for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Understanding the interaction between the virus and this receptor is essential to comprehending how the infection establishes itself and causes systemic illness. ACE2 allows the viral particle to breach the host cell membrane and begin the process of replication. The discovery of this biological gateway has informed both the medical understanding of COVID-19 pathology and the development of targeted therapeutic countermeasures.
The Normal Function of ACE2
Angiotensin-Converting Enzyme 2 is an enzyme that functions as a key regulator within the Renin-Angiotensin System (RAS), a hormonal cascade that controls blood pressure, fluid balance, and inflammation in the body. In a healthy state, ACE2 acts in a counter-regulatory capacity to maintain balance within this system. It achieves this primarily by cleaving the potent vasoconstrictor hormone Angiotensin II (Ang II).
This enzymatic process converts the pro-inflammatory and vessel-constricting Ang II into the protective peptide Angiotensin 1-7 (Ang 1-7). Ang 1-7 then acts through its own receptor, Mas, to promote vasodilation—the widening of blood vessels—and exert anti-inflammatory and anti-fibrotic effects. This ACE2-Ang 1-7 axis is generally protective, particularly in the cardiovascular system, lungs, and kidneys.
The Mechanism of Viral Entry
The entry of SARS-CoV-2 into a host cell is initiated by a precise molecular docking maneuver involving the virus’s surface protein and the ACE2 receptor. The virus is covered in characteristic Spike (S) proteins, which are glycoproteins that mediate the attachment and fusion process. The S protein is divided into two functional subunits: S1, which is responsible for attachment, and S2, which mediates the fusion of the viral and host membranes.
Within the S1 subunit is the Receptor Binding Domain (RBD), which functions as the molecular key that specifically recognizes and binds to the ACE2 receptor on the host cell surface. This high binding affinity contributes to the virus’s efficient infectivity in humans. Once the RBD is securely docked onto ACE2, the S protein must be “primed” for the final step of membrane fusion.
This priming is carried out by host cell proteases, most notably the transmembrane serine protease 2 (TMPRSS2), which is frequently co-expressed with ACE2 on target cells. TMPRSS2 cleaves the S protein, a step that is necessary to expose the fusion machinery in the S2 subunit. This cleavage allows the virus and cell membranes to merge, enabling the viral genetic material—the single-stranded RNA—to be released into the cell cytoplasm to begin replication.
Widespread Impact on Organ Systems
The reason COVID-19 presents as a multi-systemic illness is directly related to the widespread distribution of ACE2 receptors throughout the body. ACE2 is highly expressed in the epithelial cells of the lungs, specifically the type II alveolar cells, making the respiratory system the primary site of infection and a major target for damage. Infection in the lungs often leads to diffuse alveolar damage and inflammation, which can progress to acute respiratory distress syndrome (ARDS).
Beyond the lungs, significant concentrations of ACE2 are found in the heart, kidneys, and vascular endothelium lining the blood vessels. When the virus binds to the receptor, it causes the cell to internalize or shed the ACE2 protein from the cell surface, effectively downregulating its presence. This loss of membrane-bound ACE2 prevents the conversion of Ang II into protective Ang 1-7.
The resulting imbalance in the RAS leads to an overabundance of Ang II, which acts unopposed through its receptor (AT1R) to promote vasoconstriction, inflammation, and cellular damage. This systemic disruption of the protective ACE2-Ang 1-7 axis contributes to myocarditis (heart inflammation) and acute kidney injury. Damage to the endothelium is also a major consequence. Endothelial dysfunction is linked to the clotting and vascular damage seen in severe COVID-19 cases.
Therapeutic Strategies Targeting ACE2
Knowledge of the ACE2 pathway has accelerated the development of targeted medical interventions designed to prevent or mitigate infection. One successful strategy involves blocking the interaction between the viral Spike protein and the ACE2 receptor. This is achieved using neutralizing monoclonal antibodies, which are designed to bind specifically to the Spike protein’s RBD, effectively shielding the ACE2 receptor from recognition by the virus.
A second, more direct approach involves the use of soluble ACE2 (sACE2) as a decoy receptor. This synthetic version of the receptor is introduced into the body, where it circulates freely and is not attached to cell membranes. Soluble ACE2 acts as a trap, binding to the SARS-CoV-2 virus particles before they can reach the ACE2 receptors on host cells. This decoy strategy aims to neutralize the virus while preserving the protective enzymatic function of the native, membrane-bound ACE2.