The emergence of COVID-19 prompted scientific focus on how the SARS-CoV-2 virus infects human cells. Viruses require a specific entry point to infect a cell, often likened to a key fitting into a lock. For the virus that causes COVID-19, a protein known as Angiotensin-Converting Enzyme 2 (ACE2) acts as this lock. The ACE2 receptor provides the precise molecular doorway needed for the virus to initiate an infection. Understanding this relationship is important for grasping how the virus operates and for developing medical treatments.
The Normal Function of ACE2 in the Body
Before its association with COVID-19, ACE2 was studied for its role in the renin-angiotensin system (RAS), a hormonal network that regulates blood pressure and fluid balance. ACE2 is an enzyme on the outer surface of cells in organs including the lungs, heart, kidneys, and intestines. Its main job is to act as a counter-regulatory force against another enzyme, angiotensin-converting enzyme (ACE). While ACE produces a peptide called angiotensin II, which constricts blood vessels and promotes inflammation, ACE2 does the opposite.
ACE2 converts angiotensin II into angiotensin (1-7), a molecule with protective effects like dilating blood vessels and reducing inflammation. In this capacity, ACE2 functions as a brake on the RAS. This helps to maintain balance and prevent the potentially damaging effects of excessive angiotensin II activity.
How SARS-CoV-2 Uses ACE2 to Enter Cells
The SARS-CoV-2 virus is covered in spike proteins. A specific segment of this spike protein, the receptor-binding domain (RBD), has a structure highly compatible with the human ACE2 receptor. This high-affinity binding is the first step of infection, where the virus docks onto the surface of a host cell. The bond between the SARS-CoV-2 spike protein and human ACE2 is 10 to 20 times stronger than that of the original SARS virus, which may contribute to its efficient spread.
Once the spike protein’s RBD latches onto an ACE2 receptor, the host cell’s own enzymes, such as TMPRSS2, cut the spike protein. This activates it and initiates the fusion of the viral envelope with the cell membrane. This process creates an opening through which the virus can release its genetic material, RNA, into the cell’s interior.
The viral RNA then hijacks the host’s cellular machinery. It forces the cell to stop its normal functions and instead start producing copies of the virus. The cell becomes a factory for new viral particles, which are then released to infect neighboring cells, continuing the cycle of infection.
ACE2’s Influence on COVID-19 Symptoms and Severity
The wide distribution of ACE2 receptors throughout the body explains the multi-organ impact of COVID-19. High concentrations of ACE2 are found in the lungs, which is why respiratory symptoms are hallmarks of the disease. The presence of ACE2 in the heart and blood vessels is linked to cardiovascular complications like myocarditis, while receptors in the gastrointestinal tract can lead to symptoms like diarrhea and nausea.
A significant way the virus causes harm involves a process called downregulation. When the SARS-CoV-2 virus binds to an ACE2 receptor, the entire complex is often pulled into the cell. This removes the protective ACE2 enzyme from the cell surface, meaning it can no longer perform its normal function.
This disruption throws the local renin-angiotensin system out of balance. The resulting accumulation of unopposed angiotensin II can amplify inflammation, increase blood pressure, and cause injury to tissues already under attack by the virus. This mechanism is thought to contribute to the severity of the disease, particularly the development of acute respiratory distress syndrome (ARDS), where lung inflammation becomes widespread and life-threatening.
Therapeutic Strategies Targeting the ACE2 Pathway
Understanding the ACE2-virus interaction has guided the development of new treatments. One strategy involves creating molecules that block the virus from attaching to ACE2. This includes research into human recombinant soluble ACE2 (hrsACE2), which are engineered, free-floating versions of the receptor. These “decoy” receptors circulate in the body and bind to the virus before it can reach cells, effectively neutralizing it.
Another approach uses monoclonal antibodies designed to specifically target the spike protein’s receptor-binding domain, physically preventing it from latching onto ACE2. At the pandemic’s outset, there was also concern that common blood pressure medications, such as ACE inhibitors and angiotensin II receptor blockers (ARBs), could be harmful. The worry was that these drugs might increase the number of ACE2 receptors on cells, potentially making infections worse.
However, subsequent large-scale clinical studies have not supported this initial fear. Major health organizations have concluded that these medications are safe for COVID-19 patients and that they should continue taking them as prescribed. Some research even suggests these drugs might be beneficial by helping to rebalance the renin-angiotensin system.