The ACE2 Receptor and Its Connection to COVID-19
The COVID-19 pandemic highlighted the Angiotensin-converting enzyme 2 (ACE2) receptor, a protein on human cells. This receptor is the primary gateway for the SARS-CoV-2 virus to enter and infect human cells. Understanding ACE2 is central to comprehending how the virus operates and causes diverse effects in individuals. Present across various tissues, ACE2 plays a dual role: as a normal physiological regulator and as a viral entry point.
The ACE2 Receptor’s Normal Role
The ACE2 receptor is a protein found on the surface of many cell types, including those in the lungs, heart, kidneys, blood vessels, and gastrointestinal tract. Its widespread distribution highlights its diverse physiological functions, primarily regulating the renin-angiotensin-aldosterone system (RAAS). The RAAS is a complex hormonal system that controls blood pressure, fluid balance, and inflammation.
ACE2 counter-regulates another enzyme, ACE, by breaking down angiotensin II into angiotensin 1-7. Angiotensin II constricts blood vessels and promotes inflammation, contributing to higher blood pressure and tissue damage. In contrast, angiotensin 1-7 dilates blood vessels, reduces inflammation, and protects organs, balancing angiotensin II’s effects. This enzymatic activity helps maintain cardiovascular health and protects various organs from injury. Its presence in different tissues allows it to exert localized protective effects, such as reducing fibrosis in the heart or promoting repair in the lungs.
How SARS-CoV-2 Uses ACE2 for Entry
The SARS-CoV-2 virus exploits the ACE2 receptor to initiate infection. The virus has a distinctive “spike” protein on its surface, which acts like a key designed to bind to the ACE2 receptor, functioning as a lock. This binding is the first step in the viral infection process. The spike protein’s receptor-binding domain (RBD) attaches to the extracellular domain of the ACE2 protein.
Once the spike protein binds to ACE2, cellular processes facilitate viral entry. Host cell proteases, such as TMPRSS2, cleave the spike protein, a necessary step for viral activation. This cleavage allows the viral and cell membranes to fuse, enabling the viral genetic material to enter the host cell. SARS-CoV-2 essentially hijacks the ACE2 receptor, turning a beneficial host protein into a gateway for infection.
ACE2 and COVID-19 Disease Impact
The interaction between SARS-CoV-2 and the ACE2 receptor has profound implications for COVID-19 progression and severity. When the virus binds to ACE2, it can lead to a decrease in available ACE2 receptors on the cell surface, known as downregulation. This reduction in functional ACE2 can disrupt the RAAS balance, leading to angiotensin II accumulation. Elevated angiotensin II can promote inflammation, increase vascular permeability, and contribute to organ damage, particularly in the lungs.
This RAAS disruption contributes to severe lung injury and acute respiratory distress syndrome (ARDS) in many COVID-19 patients. The widespread expression of ACE2 in organs beyond the lungs, such as the heart, kidneys, and gut, explains the multi-organ involvement in severe COVID-19 cases. Individuals with pre-existing conditions like hypertension, diabetes, or heart disease may have altered ACE2 expression or RAAS dysregulation, potentially making them more susceptible to severe outcomes. Older adults often have different ACE2 expression patterns, which might contribute to their higher risk of severe illness.