ACE2, or angiotensin-converting enzyme 2, is a protein on the surface of human cells that SARS-CoV-2 latches onto to start an infection. Before the pandemic, ACE2 was a relatively obscure molecule studied mainly by cardiovascular researchers for its role in regulating blood pressure. Its hijacking by the virus that causes COVID-19 turned it into one of the most scrutinized proteins in modern biology, with consequences that reach well beyond the lungs.
What ACE2 Normally Does
ACE2 sits on the outer surface of cells in many organs, where it performs a quiet but important job: it breaks down a hormone called angiotensin II. Angiotensin II is a potent signal that constricts blood vessels and raises blood pressure. ACE2 clips angiotensin II into a smaller fragment called angiotensin 1-7, which has roughly the opposite effect, relaxing blood vessels and reducing inflammation.1PubMed Central. ACE2, a new regulator of the renin-angiotensin system In this way, ACE2 acts as a counterbalance within the body’s blood-pressure regulation system, preventing angiotensin II from pushing things too far in one direction.
But ACE2 wears more than one hat. It also functions as a partner for a protein called B0AT1 that helps transport amino acids, particularly tryptophan, across the lining of the gut.2PubMed Central. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System In animal studies, knocking out ACE2 reduced tryptophan uptake, altered the gut’s microbial community, and increased susceptibility to intestinal inflammation.3PubMed Central. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection The structural basis for this partnership was captured early in the pandemic when researchers resolved the full-length ACE2 protein bound to B0AT1 using cryo-electron microscopy, revealing that the complex forms a dimer of two ACE2-B0AT1 pairs that can shift between open and closed positions.4PubMed Central. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
How SARS-CoV-2 Exploits ACE2 to Enter Cells
The spike protein that studs the surface of SARS-CoV-2 contains a region called the receptor-binding domain, or RBD, that fits into a groove on ACE2’s surface. Compared with the original SARS virus from 2003, SARS-CoV-2’s spike makes more contacts with human ACE2, including additional hydrogen bonds and hydrophobic interactions, which results in tighter binding.5Scientific Reports. In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin One structural analysis estimated the binding energy of SARS-CoV-2’s spike to ACE2 at roughly −15.7 kcal/mol, compared with −14.1 kcal/mol for the original SARS virus, a meaningful jump driven partly by longer loop structures on the newer spike.6PubMed Central. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis
Binding alone does not get the virus inside a cell. After the spike docks onto ACE2, it needs to be cut by host enzymes so the virus can fuse with the cell membrane. Two enzymes do this work at different sites on the spike. Furin clips the spike at one location, called S1/S2, while a second enzyme called TMPRSS2 cuts at a nearby site called S2′.7Life Science Alliance. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells The two enzymes cannot substitute for each other; both cuts are needed for the virus to replicate efficiently in human airway cells. Blocking both furin and TMPRSS2 at the same time completely prevented infection in laboratory experiments, which has spurred interest in combination antiviral strategies targeting these proteases.8PubMed Central. Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity
Once the spike has been primed by these enzymes, the virus can enter the cell either by fusing directly at the surface or by being swallowed into the cell through a process called clathrin-mediated endocytosis, where the cell essentially wraps around the virus and pulls it inward. Experiments using spike-coated particles showed that blocking this engulfment pathway reduced infectivity, confirming it is an important route of entry.9Journal of Biological Chemistry. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis Which pathway the virus favors depends partly on which enzymes are available at the cell surface; cells rich in TMPRSS2 tend to support surface fusion, while cells with less of it push the virus toward the endosomal route.10PubMed Central. SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry
Where ACE2 Shows Up in the Body and Why That Matters
COVID-19 is often described as a respiratory illness, but ACE2 is not concentrated in the airways. In fact, protein-level mapping found that ACE2 is most abundant in the small intestine’s lining cells, kidney tubules, the gallbladder, heart muscle cells, and male reproductive tissue, with only limited expression detected in the respiratory system.11PubMed Central. The protein expression profile of ACE2 in human tissues An earlier study looking at SARS-CoV-1 had highlighted ACE2’s presence on the surface of lung alveolar cells and small-intestine enterocytes, along with blood vessel walls throughout the body.12PubMed Central. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus
This distribution helps explain the wide range of symptoms people experience. Gastrointestinal complaints like diarrhea and nausea, common in COVID-19, track with the heavy ACE2 expression on gut lining cells. ACE2’s role in tryptophan absorption means that viral hijacking of the receptor could disrupt amino acid uptake, alter gut bacteria, and promote intestinal inflammation.3PubMed Central. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection Cardiac complications, including myocarditis, also track with ACE2’s presence on heart muscle cells; changes in ACE2 levels during infection and the exaggerated immune response that follows may both contribute to heart injury.13PubMed Central. COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors
Loss of smell, one of the earliest and most recognizable COVID-19 symptoms, offers another instructive case. Researchers initially assumed the virus was attacking olfactory neurons directly, but single-cell analysis showed that ACE2 is not found on the smell-sensing neurons themselves. Instead, it is expressed on the support cells surrounding them and on the cells lining nearby blood vessels. Infection of these support cells appears to damage the environment that olfactory neurons need to function, leading to smell disturbances without directly infecting the neurons.14PubMed Central. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
How Infection Disrupts ACE2’s Normal Function
When SARS-CoV-2 binds ACE2, it does not leave the receptor intact on the cell surface. The act of viral entry triggers a cascade that sharply reduces the amount of ACE2 available to do its normal job. Laboratory experiments showed that among all 26 viral proteins tested, only the spike protein caused a dose-dependent drop in ACE2 levels.15Journal of Infection. Spike-mediated ACE2 down-regulation was involved in the pathogenesis of SARS-CoV-2 infection The same study found that angiotensin II levels were significantly elevated in COVID-19 patients compared with healthy controls, and that high angiotensin II promoted the death of pulmonary artery endothelial cells, driving vasoconstriction, inflammation, and blood clotting.
This loss of ACE2 happens through several mechanisms: the virus pulls ACE2 into the cell during entry, the spike triggers an enzyme called ADAM17 to cut ACE2 off the cell surface (a process called shedding), and the virus suppresses the interferon signals that normally help maintain ACE2 expression.16Current Drug Targets. Downregulation of Membrane-bound Angiotensin Converting Enzyme 2 (ACE2) Receptor has a Pivotal Role in COVID-19 Immunopathology The ACE2 fragments shed from the cell surface, called soluble ACE2, retain their enzymatic activity and can still bind spike protein. Whether circulating soluble ACE2 helps or hurts during infection remains debated; it could theoretically block viral entry by acting as a decoy, but it might also ferry viral particles to new cells.17PubMed Central. Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients
Blood Pressure Medications and the ACE2 Debate
Early in the pandemic, a heated debate erupted over whether common blood pressure drugs were making COVID-19 worse. ACE inhibitors and angiotensin receptor blockers (ARBs), taken by hundreds of millions of people worldwide, were known to affect the same hormonal system that ACE2 regulates. Some researchers worried these drugs might increase ACE2 expression, giving the virus more doorways into cells. Others argued the drugs’ protective cardiovascular effects would outweigh any theoretical risk. Major cardiology societies urged patients not to stop their medications, but the question needed a proper trial.
The BRACE CORONA trial in Brazil provided that answer. It randomized hospitalized COVID-19 patients who were already taking ACE inhibitors or ARBs to either continue or stop them. The overall result showed no meaningful difference: patients who stopped had an average of about 22 days alive and out of the hospital over 30 days, compared with roughly 23 days for those who continued.18JAMA. Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19 A closer look at patients grouped by disease severity added nuance: those with mild COVID-19 fared similarly regardless of what they did with their medications, but those with moderate disease actually did worse when they stopped their medications, with roughly two fewer days alive and out of the hospital compared to those who continued.19PubMed Central. Discontinuing vs continuing ACEIs and ARBs in hospitalized patients with COVID-19 according to disease severity: Insights from the BRACE CORONA trial The practical takeaway: stopping these drugs during COVID-19 did not help, and for sicker patients it may have been harmful.
Soluble ACE2 as a Biomarker for Severity
The fragments of ACE2 that get shed into the bloodstream during infection have drawn interest as a possible early warning signal. One study of hospitalized COVID-19 patients found that higher baseline levels of plasma ACE2 at admission were significantly associated with worse outcomes over 28 days, with an odds ratio of about 1.8 for progressing to severe disease. That association held even after adjusting for age, obesity, high blood pressure, and standard lab markers like C-reactive protein and D-dimer.20PLoS ONE. Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients A separate analysis found that combining soluble ACE2 levels with the aldosterone-to-renin ratio and a genetic marker for TMPRSS2 yielded a reasonably strong predictive model for COVID-19 severity.21PubMed Central. A low aldosterone/renin ratio and high soluble ACE2 associate with COVID-19 severity
However, the picture is not entirely clean. Another study found that soluble ACE2 levels did not differ between patients who died and those who survived, and did not track with the level of respiratory support required.22PubMed Central. Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers This discrepancy may reflect timing: soluble ACE2 spikes transiently early in disease and may be more useful as an admission-day snapshot than as a running indicator. It has not become a standard clinical test.
Why Children Seemed More Protected
One of the persistent puzzles of the pandemic was why children generally experienced milder COVID-19 than adults. ACE2 expression levels in the nose, the virus’s first point of contact, turned out to be part of the story. A study comparing nasal tissue from children and adults found that ACE2 gene expression increased with age, even after accounting for sex and asthma status, leading researchers to propose that children’s lower nasal ACE2 levels may limit the initial viral foothold.23JAMA. Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults Differences in how the ACE2 gene is methylated (a chemical modification that affects gene activity) in children’s nasal cells have also been documented, suggesting an additional layer of regulation beyond simple gene expression levels.24Scientific Reports. DNA methylation architecture of the ACE2 gene in nasal cells of children
The picture is not fully settled, though. One study of nasal and oral tissue actually found that pediatric samples had about 43% more nasal ACE2 RNA than adult samples.25PubMed Central. ACE2 and TAS2R38 receptor expression in pediatric and adult patients in the nasal and oral cavity This contradiction highlights a broader issue in ACE2 research: measuring RNA does not always predict how much protein ends up on the cell surface, and different tissue-sampling methods can yield different answers. Most researchers agree that ACE2 expression is only one piece of why children fare better, alongside differences in immune maturity, innate immune responses, and cross-reactive immunity from other coronaviruses.
Genetic Variation in ACE2 and Individual Susceptibility
Because ACE2 is the virus’s doorway, natural differences in the ACE2 gene could plausibly make some people more or less vulnerable. Researchers have catalogued many naturally occurring variants, and a few stand out. The ACE2 D355N variant, for example, was found to restrict spike protein binding and limit infection both in cell culture and in animal models, raising the possibility that people carrying it might have some built-in resistance.26PubMed Central. Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection An analysis of the Italian population identified several missense variants predicted to affect ACE2’s structure or its interaction with the spike protein, including some that might interfere with the internalization step after the virus binds.27European Journal of Human Genetics. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
Beyond the receptor itself, genetic variants near the ACE2 gene have been linked to other health conditions. One study found that a specific variant (rs2074192) in the ACE2 gene was associated with increased risk of high blood pressure in obese men who smoked, but not in lean men, non-smoking men, or women, pointing to complex gene-environment-sex interactions.28PubMed Central. SARS–CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking The ACE2 gene sits on the X chromosome, which means biological males carry only one copy while females carry two. This has fueled speculation about whether sex-based differences in ACE2 contribute to the generally worse COVID-19 outcomes seen in men, though disentangling genetic effects from hormonal and behavioral factors has proven difficult.
How the Virus Evolved Its Grip on ACE2
SARS-CoV-2 did not maintain a static relationship with ACE2 as it mutated through successive waves. The Omicron BA.1 variant, which swept the world in late 2021, actually bound human ACE2 with significantly lower affinity than the original strain or the Alpha variant. This was a surprise: Omicron’s explosive spread was apparently driven more by immune evasion than by tighter receptor binding.29PubMed. Mutations in the SARS-CoV-2 spike proteins affected the ACE2-binding affinity during the development of Omicron pandemic variants Later Omicron subvariants like BA.5 and XBB.1.5 recovered and even exceeded the original strain’s ACE2 affinity, suggesting that once the virus had escaped enough of the population’s immune defenses, selection pressure swung back toward better receptor binding.
Researchers studying more recent lineages like JN.1, KP.2, and KP.3 found evidence for a specific evolutionary balancing act. Mutations at certain positions in the spike’s receptor-binding domain weakened antibody recognition but also impaired ACE2 binding. Compensatory mutations at nearby positions then restored receptor affinity through cooperative effects, allowing the virus to evade immunity without paying a fitness cost in cell entry.30PubMed Central. AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants This cat-and-mouse dynamic between immune escape and receptor attachment is a central challenge for vaccine design: every time the virus changes its spike to dodge antibodies, it may alter ACE2 binding in ways that affect transmissibility.
One intriguing finding from binding studies with early Omicron strains is that Alpha and Omicron variants could bind mouse ACE2, whereas the original virus could not. This led some researchers to hypothesize that early Omicron strains may have evolved in a rodent host before crossing back into humans, accumulating a burst of mutations adapted to a different ACE2 sequence.29PubMed. Mutations in the SARS-CoV-2 spike proteins affected the ACE2-binding affinity during the development of Omicron pandemic variants
ACE2 Across Species
ACE2 is not unique to humans. An analysis of ACE2 sequences from 410 vertebrate species found that only mammals had enough similarity at the key binding residues to plausibly support SARS-CoV-2 infection, with Old World primates (the group that includes humans, great apes, and some monkeys) scoring the highest risk. The number of unfavorable amino acid changes at the binding interface correlated strongly with predicted binding score across species.31PubMed Central. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates A separate comparative analysis confirmed that many animal ACE2 proteins lack certain hydrophobic contacts present in human ACE2, making them less hospitable to the virus.32PubMed Central. Comparative analyses of ACE2 and TMPRSS2 gene: Implications for the risk to which vertebrate animals are susceptible to SARS-CoV-2
These predictions have largely been borne out in practice. White-tailed deer, mink, cats, and hamsters have all shown susceptibility to infection, while many other mammals appear resistant. The breadth of potential hosts matters because animal reservoirs can harbor the virus, allow it to accumulate mutations, and potentially seed new variants back into human populations.
Engineered ACE2 Decoys as a Therapeutic Strategy
If ACE2 is the lock the virus picks, one creative defense is to flood the scene with fake locks. Engineered soluble ACE2 molecules, sometimes called decoys, are designed to mimic the receptor and soak up viral spike protein before it can reach real cells. Several research groups have taken this idea from concept to preclinical testing.
One major advantage decoys hold over monoclonal antibodies is resilience against viral escape. Deep mutational scanning showed that an engineered ACE2 decoy prevented viral escape across every single-residue mutation tested in the receptor-binding domain, a feat no individual antibody could match. The same decoy neutralized the Omicron variant as effectively as the original Wuhan strain and showed therapeutic benefit in hamsters and mice engineered to express human ACE2.33PubMed Central. An engineered ACE2 decoy neutralizes the SARS-CoV-2 Omicron variant and confers protection against infection in vivo A separate group generated escape mutants against wild-type ACE2 decoys and monoclonal antibodies in the lab but found that their high-affinity engineered decoy resisted escape entirely, including against Omicron subvariants like XBB and BQ.1 that had already rendered clinical antibodies useless. Delivering this decoy as an inhaled aerosol improved outcomes in rodents at one-twentieth the dose needed for intravenous delivery and showed efficacy in non-human primates.34PubMed. An inhaled ACE2 decoy confers protection against SARS-CoV-2 infection in preclinical models
The engineering behind these decoys is getting increasingly precise. A computationally designed variant called FLIF bound the Delta variant’s receptor-binding domain with roughly 80-fold greater affinity than natural ACE2, driven by just a handful of strategic amino acid changes.35Communications Biology. A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo Because any SARS-CoV-2 variant that evolved to dodge the decoy would also lose the ability to bind the real receptor and enter cells, the virus faces a dead-end evolutionary trap. This built-in escape resistance makes ACE2 decoys appealing not just for current variants but as a hedge against future ones, including entirely new coronaviruses that use ACE2 as their entry point.
Smoking, Obesity, and ACE2 Expression
Among lifestyle factors that could affect susceptibility through ACE2, smoking received early attention. Gene expression studies found that tobacco smoking increased ACE2 levels in lung tissue, though the same datasets did not show a clear association between age or sex and ACE2 or furin expression. Interestingly, TMPRSS2 expression showed a negative correlation with age in some datasets, complicating any simple narrative about older people having “more” of the viral entry machinery.36PubMed Central. Tobacco Smoking Increases the Lung Gene Expression of ACE2, the Receptor of SARS-CoV-2 The relationship between smoking, ACE2 levels, and COVID-19 outcomes remained contentious throughout the pandemic, in part because smokers also tend to have other risk factors that are hard to untangle from a single gene’s expression level.
Obesity adds another layer. The ACE2 gene variant rs2074192 was linked to hypertension risk specifically in obese male smokers, with an odds ratio of about 1.67 compared with non-carriers. That same variant was not a risk factor in lean men, non-smokers, or women, illustrating how genetic susceptibility through ACE2 can depend heavily on what other conditions are present.28PubMed Central. SARS–CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking Fat tissue itself expresses ACE2, and the chronic low-grade inflammation characteristic of obesity tends to upregulate components of the hormonal system ACE2 regulates, potentially amplifying the damage when ACE2 gets pulled off the playing field by infection.