Unlocking the molecular secrets behind COVID-19 infection
Viral Entry Mechanism
ACE2 Receptor
Therapeutic Implications
When SARS-CoV-2 began its global spread in late 2019, scientists faced a critical question: how does this virus actually enter our cells? The answer emerged from earlier research on the original SARS virus from 2003—a humble protein called ACE2 (angiotensin-converting enzyme 2). This previously obscure enzyme, present on the surface of our cells, serves as the essential entry receptor that allows the virus to dock and invade our bodies.
The discovery that ACE2 acts as SARS-CoV-2's cellular gateway has revolutionized our understanding of COVID-19, explaining why the virus affects not just our lungs but multiple organs, and opening promising avenues for treatment. This article explores the fascinating science behind this critical receptor and the pivotal experiments that revealed its role in the pandemic virus that changed our world.
ACE2 serves as the primary entry point for SARS-CoV-2, explaining the multi-organ nature of COVID-19 and providing targets for therapeutic intervention.
Long before SARS-CoV-2 emerged, ACE2 played crucial roles in maintaining our health. This protein is part of the renin-angiotensin system (RAS), which regulates blood pressure, fluid balance, and vascular resistance 2 4 . ACE2 primarily functions as an enzyme that catalyzes the conversion of angiotensin II (a peptide that causes vasoconstriction and inflammation) to angiotensin 1-7 (which has vasoprotective effects) 3 4 . In simple terms, ACE2 acts as a counterbalance to the more damaging aspects of the hormone system that controls blood pressure.
ACE2 also facilitates amino acid transport in the small intestine and affects heart function 3 . Its presence in multiple tissues explains why COVID-19 can manifest with symptoms beyond respiratory issues, including gastrointestinal problems and cardiac complications 7 .
Converts angiotensin II to angiotensin 1-7, reducing blood pressure
Facilitates nutrient absorption in the small intestine
Plays a role in maintaining heart health
Counters inflammatory pathways in various tissues
ACE2 is expressed in various human tissues, though at different levels 7 :
| Tissue/Organ | ACE2 Expression Level | Clinical Significance in COVID-19 |
|---|---|---|
| Small intestine |
|
May explain gastrointestinal symptoms |
| Testis |
|
Potential impact on reproductive health |
| Kidneys |
|
Linked to acute kidney injury in severe cases |
| Heart |
|
Associated with cardiac complications |
| Thyroid |
|
Possible endocrine involvement |
| Lungs |
|
Primary site of infection despite medium expression |
| Liver |
|
May contribute to liver function abnormalities |
| Colon |
|
Could explain digestive symptoms |
| Blood vessels |
|
May still enable vascular infection and clotting issues |
| Brain |
|
Potential route for neurological symptoms |
This widespread distribution of ACE2 throughout the body provides a biological basis for the multi-organ nature of COVID-19, where the virus can damage not just the lungs but also the heart, kidneys, digestive system, and other organs 4 7 .
The SARS-CoV-2 virus possesses a crown-like structure (hence the name "corona") made up of spike (S) proteins that protrude from its surface 5 . These spike proteins are the virus's molecular keys that unlock our cells. Each spike protein consists of two subunits: S1, which contains the receptor-binding domain (RBD) that directly attaches to ACE2, and S2, which enables fusion with our cell membranes 5 9 .
What makes SARS-CoV-2 particularly effective is the structural precision of its RBD, which fits into ACE2 like a key in a lock 9 . Research has revealed that SARS-CoV-2's spike protein binds to ACE2 with 10-20 times higher affinity than the original SARS virus from 2003, potentially explaining its greater transmissibility 4 .
The S1 subunit contains the Receptor-Binding Domain (RBD) that attaches to ACE2, while the S2 subunit mediates membrane fusion.
Viral entry follows an elegant multi-step process 5 :
The spike protein's RBD recognizes and binds to ACE2 on human cells
Cellular proteases (including TMPRSS2) cleave the spike protein, priming it for membrane fusion
The viral membrane fuses with the human cell membrane
The viral genetic material enters the cell, hijacking its machinery to produce more viruses
This sophisticated entry mechanism highlights why understanding the ACE2-spike interaction has been so crucial to developing treatments and vaccines.
In early 2020, as SARS-CoV-2 spread globally, scientists needed to confirm whether ACE2 truly served as the functional receptor. Researchers used several innovative approaches to answer this critical question 9 :
Scientists created harmless "pseudoviruses" engineered to express the SARS-CoV-2 spike protein but lacking other viral components. These pseudoviruses could enter cells but not cause full infection, allowing safe study of the entry process 9 .
Researchers introduced soluble ACE2 protein into cell cultures before exposing them to SARS-CoV-2. If ACE2 was indeed the receptor, this soluble version would act as decoy, binding to the virus and preventing it from attaching to actual cells 1 9 .
Using advanced gene-editing techniques, scientists created cells lacking the ACE2 gene and compared their susceptibility to infection with normal cells expressing ACE2 9 .
The findings from these experiments provided compelling evidence:
| Experimental Approach | Key Finding | Significance |
|---|---|---|
| Pseudovirus infection | Pseudoviruses with SARS-CoV-2 spike protein could only enter cells expressing ACE2 | Established ACE2 as necessary for viral entry |
| Soluble ACE2 competition | Soluble ACE2 blocked over 90% of viral infection | Confirmed specific interaction between spike and ACE2 |
| ACE2 knockout cells | Cells lacking ACE2 were largely resistant to infection | Demonstrated ACE2 is essential for viral entry |
| Antibody blocking | Anti-ACE2 antibodies prevented viral entry | Provided additional evidence for ACE2's role as primary receptor |
These experiments collectively proved that ACE2 isn't just one of many potential receptors—it's the critical gateway that SARS-CoV-2 exploits to invade our cells 9 . The research also quantified the strength of this interaction, revealing that SARS-CoV-2 binds to ACE2 with remarkably high affinity, with dissociation constants (Kd) in the nanomolar range (approximately 1-31 nM depending on the study) 1 9 .
The experimental evidence confirmed ACE2 as the essential receptor for SARS-CoV-2, with binding affinity 10-20 times stronger than the original SARS virus, potentially explaining its higher transmissibility.
Studying viral entry requires specialized reagents and tools. Here are some essential components of the SARS-CoV-2 researcher's toolkit:
| Research Tool | Composition/Type | Research Application |
|---|---|---|
| Recombinant ACE2 protein | Soluble human ACE2 extracellular domain | Serves as decoy receptor to block viral entry; measures binding affinity |
| Spike pseudotyped viruses | Lentiviral or vesicular stomatitis virus vectors with SARS-CoV-2 spike | Enables safe study of viral entry without high-containment facilities |
| Anti-ACE2 antibodies | Monoclonal and polyclonal antibodies | Blocks ACE2-spike interaction; detects ACE2 expression in tissues |
| SARS-CoV-2 spike RBD | Recombinant receptor-binding domain protein | Measures binding kinetics and affinity for ACE2 |
| TMPRSS2 inhibitors | Small molecule protease inhibitors (camostat, nafamostat) | Blocks spike protein priming and reduces viral entry |
| ACE2 knockout cell lines | Genetically modified cells lacking ACE2 | Controls to confirm ACE2-dependent entry mechanisms |
These research tools have been instrumental not only in understanding how SARS-CoV-2 enters cells but also in developing therapeutic strategies to block this entry 5 9 .
The discovery of ACE2 as SARS-CoV-2's receptor has helped explain several puzzling aspects of COVID-19:
The widespread distribution of ACE2 throughout the body explains why COVID-19 can affect lungs, heart, kidneys, intestines, and other organs 4 7 .
After SARS-CoV-2 binds to ACE2, the receptor-virus complex is often internalized, reducing surface ACE2 levels. This downregulation may disrupt the protective ACE2/angiotensin 1-7 axis, potentially exacerbating tissue damage and inflammation 1 3 .
Conditions like hypertension, diabetes, and cardiovascular disease are associated with worse COVID-19 outcomes. Interestingly, these conditions often involve alterations in the renin-angiotensin system where ACE2 plays a key role 9 .
Understanding ACE2's role has inspired multiple therapeutic approaches:
Administering soluble ACE2 as a decoy receptor could soak up viral particles before they reach cell surfaces 1 3 . Early clinical trials showed that recombinant human ACE2 could reduce plasma angiotensin II levels and increase angiotensin 1-7, potentially addressing both viral entry and the imbalance in the renin-angiotensin system 3 .
Monoclonal antibodies that target either ACE2 or the spike protein's RBD can prevent their interaction. This approach has led to effective antibody treatments for COVID-19 5 .
Most COVID-19 vaccines target the spike protein to generate antibodies that block its interaction with ACE2, preventing viral entry 5 .
The discovery of ACE2 as SARS-CoV-2's primary receptor has directly informed multiple therapeutic strategies, from decoy receptors and monoclonal antibodies to vaccines that target the spike-ACE2 interaction.
The identification of ACE2 as SARS-CoV-2's critical in vivo receptor represents a triumph of molecular biology that has directly informed our pandemic response. This humble receptor, once known mainly to specialists studying blood pressure regulation, has taken center stage in one of the most significant public health crises of our time.
From explaining COVID-19's diverse symptoms across multiple organs to inspiring innovative treatments, the understanding of ACE2's role has proven invaluable. The experiments that confirmed this relationship—using pseudoviruses, receptor blocking, and genetic approaches—exemplify how basic scientific research can rapidly provide crucial insights during an emergency.
As research continues, scientists are exploring how variations in ACE2 expression might affect individual susceptibility to infection, why some species are resistant to the virus while others are vulnerable, and how we might better protect this critical receptor from future coronavirus threats. The story of ACE2 and SARS-CoV-2 reminds us that fundamental biological research, often conducted without immediate application in mind, provides the essential knowledge needed to confront unexpected challenges.
References will be listed here in the final publication.