- What is ACE2?
- ACE2 and coronavirus
- How does coronavirus attach to cells?
- ACE2 – Is more or less better for preventing and treating coronavirus?
- How likely is a coronavirus vaccine?
- Increasing or decreasing ACE2?
- Can your genes protect you against COVID-19?
- Is ACE2 the reason why women seem to fare better against COVID-19?
- Kids and coronavirus – the role of ACE2 expression
- Looking ahead to future treatments for COVID-19
ACE2 is enjoying fifteen minutes of fame thanks to a raft of new studies revealing its starring role in the COVID-19 pandemic. This cell receptor, found in lung tissue and other tissues, could hold the key to preventing and treating this devastating disease. But what do we actually know about ACE2 receptors?
Could ACE2 explain why some of us appear to be more vulnerable to COVID-19? And might this little-known cell receptor offer a way to shut the door on the virus for good?
What is ACE2?
In a healthy human, the ACE2 receptor degrades proteins called angiotensin-I and angiotensin-II to smaller peptides called angiotensin 1-9 and angiotensin 1-7, respectively.
Strangely, angiotensin-I doesn’t seem to have any function in the body. But, as you might imagine given the name, ACE2 has a predecessor, ACE1. This angiotensin converting enzyme converts angiotensin-1 into angiotensin-II, a protein that binds to angiotensin receptors on the surface of cells and has a profound effect on blood pressure, among other things.
For decades, millions of people worldwide have been taking drugs every day that inhibit these angiotensin converting enzymes. Why? Because reducing the conversion of angiotensin-I to angiotensin-II (or inhibiting conversions upstream from ACE1), helps keep blood pressure in check. In addition to ACE inhibitors, other drugs work by blocking the last binding step, antagonizing the angiotensin receptor to help treat hypertension.
For many people living with high blood pressure, the introduction of ACE1 inhibitors in the 1980s and shortly thereafter angiotensin receptor blockers (ARBs) was a lifesaver.
Now, in the age of coronavirus, many people are wondering if taking ACE inhibitors and ARBs for high blood pressure raises your risk of COVID-19.
(TL:DR – don’t suddenly stop taking your blood pressure medications. Your risk of serious health problems from untreated hypertension is likely far higher than your risk of getting coronavirus. And hypertension itself is a risk factor for dying from severe COVID-19.)
Which brings us back to coronavirus.
As the world wrestled with SARS-CoV back in 2002-2004, scientists scrambled to figure out how the virus invaded human cells. The verdict? The ACE2 receptor.1
So, when SARS-CoV-2, i.e. the coronavirus responsible for COVID-19, struck late last year, researchers turned quickly to the ACE2 receptor and, lo and behold, this receptor appears to lay out the welcome mat for this virus too.2
Think of the ACE2 receptor as the door handle that the virus latches onto to gain entry to our cells. Once inside, the virus replicates itself and can go on to wreak havoc in the body.
ACE2 is found in abundance on the surface of cells in the lungs and in the small intestine, as well as in the kidney and heart. Indeed, ACE2 expression protects the lungs against injury (more on this below).3 ACE2 receptors have also been found in the nose, which may be how the virus first takes hold before entering deeper into the body. It’s no surprise, then, that initial symptoms of COVID-19 are mainly respiratory and gastrointestinal in nature, with cardiac and kidney problems seen in more severe cases.4
So, given that ACE2 lets coronavirus into cells, it would appear to make sense that the more ACE2 receptors you have, the more likely you are to get sick with COVID-19.
Strangely, that isn’t always the case. More on that in a moment, but first let’s look at how the virus attaches to the ACE2 receptor and why this may offer hope for a treatment or even a way to prevent infection.
A paper published April 16th in the journal Cell detailed exactly how the coronavirus attaches to and enters human cells. It was already known that the virus uses spike (S) proteins to bind to cellular receptors, namely ACE2 receptors. This latest study found that the SARS-CoV-2 virus uses serine protease TMPRSS2 and endosomal cysteine proteases cathepsin B and L (CatB/L) to prime the ACE2 receptor to bind with the S protein (the virus’ spike).5
In super simple terms, the spike protein on the coronavirus needs to be cut in two places so that the virus can fuse to the cell membrane. This cutting is done by enzymes called proteases, specifically TMPRSS2 and CatB/L.
These proteases are also used by SARS-CoV to prime the ACE2 receptors, but in this latest study the researchers found a key difference between the two viruses. SARS-CoV is totally dependent on TMPRSS2 to bind to ACE2. Inhibit that enzyme and you prevent the virus from attaching to cells, regardless of the activity of CatB/L. For the virus that causes COVID-19, however, inhibiting TMPRSS2 doesn’t fully protect the cell as SARS-CoV-2 can still use CatB/L to prime ACE2 receptors.
What does this all mean? Well, in short, a drug that prevents infection with SARS-CoV might not prevent infection with SARS-CoV-2 (the cause of COVID-19). However, if scientists can find a way to fully inhibit both TMPRSS2 and CatB/L, this might do the trick.
So far, there is at least one TMPRSS2 inhibitor approved for clinical use in Japan for an unrelated condition. In laboratory studies, a drug called camostat mesylate, an inhibitor of TMPRSS2, blocks SARS-CoV-2 infection of lung cells without any unwanted toxic effects on cells (cytotoxicity).6 Whether this drug might be useful off-label for SARS-CoV-2 remains to be seen.
So far, what we don’t know about ACE2 and coronavirus far outweighs what we do. And, unsurprisingly, those gaps in knowledge have created plenty of confusion and concern. In March, for instance, the French healthy ministry warned against the prescription of NSAIDs such as ibuprofen because it could increase ACE2 receptor levels on cells. The World Health Organization and the European Medicines Agency did not follow suit. And, as mentioned above, some scientists think that increasing ACE2 might actually be helpful.
Similarly, there has been some confusion over whether people taking ACE inhibitors to control blood pressure should stop taking these drugs (they probably shouldn’t, unless advised to by a medical professional!).
As with ibuprofen, the concern was that ACE inhibitors could raise the risk of COVID-19. Doctors have rushed to calm such fears, noting that anyone who stops taking such medications faces serious risks of skyrocketing blood pressure. And the risks associated with uncontrolled hypertension are far greater than the risk of infection with coronavirus. What’s more, people with untreated high blood pressure have been seen to have a higher risk of serious illness and death from COVID-19.7
Given that ACE inhibitors are already heavily prescribed, we’d probably already know if they were a major risk factor for getting COVID-19. Additionally, classical ACE inhibitors such as captopril and lisinopril don’t inhibit ACE2 activity.8
Importantly, data from China suggests that only a fraction of people who developed COVID-19 has been previously treated with antihypertensive drugs such as ACE inhibitors. Only around 30-40% of people with hypertension in China are treated with antihypertensive therapy, seemingly, and just 25-30% of those treated are given renin-angiotensin aldosterone system (RAAS) inhibitors.9 The use of these drugs doesn’t seem to be a major driver for infection, then. Instead, older age and the hypertension and respiratory issues associated with aging are closely associated with negative outcomes from COVID-19.10
ACE2 as a target for vaccines and drugs to treat COVID-19
ACE2 could be the key to developing a treatment for COVID-19 or a vaccine against the coronavirus that causes it. Indeed, many biotech companies are focusing on ACE2 as a target for drugs to reduce risk of severe infection.
Showing the complexity of ACE2, several pharmaceutical companies are taking wildly opposite approaches to drug development. In one case, an Austrian company, Apeiron Biologics is reportedly trying to increase levels of circulating ACE2 so as to give the virus more to bind with, the idea being to overwhelm and confuse coronavirus. Alnylam Pharmaceuticals and Vir Biotechnology are collaborating to develop drugs that decrease ACE2, so the virus has less to bind to, the idea being that it would then, effectively, starve in the body.
All of this research is either in very preliminary stages or part way through clinical trials, meaning we won’t have a sense of efficacy until the late fall at the earliest.
Given this complexity, why are researchers focusing on ACE2 as a treatment target for COVID-19?
Could increasing ACE2 expression reverse lung and heart injury associated with COVID-19?
As I mentioned earlier, ACE2 receptors are the doors by which coronavirus enters cells. Once the virus is in the cell, though, it downregulates ACE2 expression.11 This prevents ACE2 from protecting tissues from the negative effects of angiotensin-II. So much so that researchers have theorized that this unchecked angiotensin-II activity may contribute to the severe lung and heart injury seen in COVID-19.12
Reduced membrane ACE2 expression in the lungs also enables infiltration of neutrophils in response to bacterial endotoxin. If you’ve heard doctors talking about ‘cytokine storms’ recently, this is what they mean.13 Basically, the body’s normal response to bacterial infection, such as with pneumonia, involves chemical messengers called cytokines that recruit immune system cells, such as neutrophils, to come and destroy the invading pathogen. This is supposed to be a short, sharp blast of inflammation and activity, after which cytokines restore homeostasis.
In the case of a cytokine storm, inflammation and immune system activity runs amok, with excessive neutrophil activity and the destruction of the body’s own tissue. So, it seems that reduced ACE2 expression in the lungs allows neutrophils to flood tissues.14 The result is a little like using a pressure washer to clean a speck of dirt from a strawberry.
In one small study, people with COVID-19 were found to have elevated levels of plasma angiotensin-II, and these higher levels were correlated with a higher viral load and greater degree of lung injury.15 In other viral infections, restoring ACE2 levels has been seen to reverse the process of lung injury and reduce angiotensin-II levels.1617 In one clinical trial, using recombinant human ACE2 helped to reduce lung injury associated with acute respiratory distress syndrome.18
This kind of treatment with ACE2 in active infection may also reduce damage to heart tissue. Again, in COVID-19, the virus’s effects include reducing ACE2 and its protective effects on the heart and lungs. Indeed, markers for myocardial injury increase as the disease worsens, especially just prior to death.19 Researchers in China were planning to look at whether recombinant ACE2 might help prevent heart injury in COVID-19 but the study has since been withdrawn.
The thing to note here is that these potential treatments tend to focus on increasing circulating levels of ACE2, not necessarily levels of ACE2 on the surface of cells. Indeed, ACE2 itself is ‘shed’ from endothelial cells and enters circulation, depending on the activity of an enzyme called ADAM17 (a disintegrin and metalloproteinase 17).20 Finding drugs that increase circulating ACE2 but reduce membrane-bound ACE2 might be the real prize.
Other studies are looking at whether people with COVID-19 fare better when given the angiotensin receptor blocker losartan (NCT04311177 / NCT04312009). Losartan is used to treat high blood pressure, diabetic kidney disease, heart failure, and left ventricular enlargement. Treatment with this drug has been seen to increase the expression of ACE2 in heart tissue.21
It’s plausible, then, that giving losartan to people with COVID-19 could help protect against heart and lung damage and improve outcomes. All of this is preliminary, however, with more study needed to figure out exactly what is going on and how ACE2 may help or hinder COVID-19 prevention and treatment.
Without an effective vaccine for coronavirus, and serious uptake, community spread remains a significant concern. But what’s the likelihood of a coronavirus vaccine in the next few months or even years?
The good news is that some of those people who recovered from SARS-CoV have been found to have antibodies that largely attack the viral S protein.2223 In fact, the same research that identified ACE2 and the S protein as the way SARS-CoV-2 invades cells suggests that SARS-CoV antibodies may also protect against SARS-CoV-2 infection.2 This all-important S protein could also be a key target for development of a vaccine for coronavirus that causes COVID-19.
One small study observed almost 100% seroconversion (i.e. antibody product in response to vaccination) after day 42 in volunteers injected with inactivated SARS coronavirus.24 In theory, this would mean all of those with antibodies would be able to quickly fight off and prevent infection with SARS CoV (more on this in a moment). Antibodies peaked two weeks after the second vaccination but decreased four weeks later.
This waning of antibodies flags up a potential problem with this vaccine against SARS-CoV and any vaccine developed against SARS-CoV-2: they may only offer short-lived protection against the virus. This could also mean that antibody levels in recovered SARS-CoV-2 patients are too low to offer any meaningful protection against reinfection.27
So far, we just don’t have enough information or sufficiently robust testing protocols to know whether a person who was infected with coronavirus can get re-infected. Some reports suggests this has occurred, but these few cases may be the result of false negatives, including where patients were deemed recovered but still carried the virus.
All in all, the development of a vaccine against coronavirus looks promising, with an established target and plenty of researchers working hard on the problem. What remains to be seen is how effective a vaccine is, how long protection lasts, whether there are side effects, and how quickly the health care system can roll out a global vaccination program. Researchers in Oxford, UK, are going full steam ahead with a vaccine, though, with promising results in monkeys.
One potential concern, which I haven’t yet seen raised by health officials, is that while labs switch capacity to researching and producing potential SARS-CoV-2 vaccines, their focus shifts away from developing seasonal flu vaccines. Come fall, this could lead to a shortage of effective flu vaccines and an even bigger challenge for the overburdened health care system.
So, what about developing an effective prophylactic treatment to prevent COVID-19 after exposure to coronavirus, in lieu of an actual vaccine?
Increasing or decreasing ACE2?
As I mentioned above, the trick to preventing COVID-19 may be to create a ‘flotilla’ of circulating ACE2, which can bind to virus in the blood and prevent it from gaining entry to cells via the receptor. That’s the calculation behind the drug being developed by Apeiron.
Apeiron’s experimental treatment, which resulted from the SARS epidemic in 2002, led to them licensing their drug to Glaxo Smith Kline in 2010. The company recently reclaimed the rights to the drug and set up another trial this year in Europe involving around 200 patients. Results are expected in late fall, but the company is taking steps to find partners so they can move quickly on production should results look promising.
In the opposite direction, Alnylam and Vir are hoping to use a gene-silencing technique (RNA interference) to mute the ACE2 receptor. Essentially, they’re hoping to remove the virus’s preferred door to our cells. The problem here, however, is that ACE2 has other important roles in the body, such as keeping blood pressure in check and modulating inflammation. Even a temporary knockout of ACE2 receptors could lead to acute spikes in blood pressure and undesirable effects on inflammatory processes.28
Added to this problem is the fact that RNA-based drugs tend to get trapped in and processed by the liver rather than getting dispersed to other tissues. The researchers at Alnylam and Vir are looking at ways to administer their drugs through inhalation or other means, so as to deliver them directly to affected lung tissue.
These two companies are also working on drugs with the potential to affect the virus itself, but there’s little detail about this research so far. It’s likely, however, that the drugs would target genes encoding one of the virus’s four major structural proteins. These comprise the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein.
Treating monkey cells with a human anti-ACE2 antibody (catalog # AF933) prevented the expression of the SARS-CoV-2 S protein in lab tests.2 This anti-ACE2 antibody is typically used in tests to detect ACE2 in tissue samples, but this time the scientists wanted to test its potential therapeutic value in preventing coronavirus transmission. So far, success in lab tests has not been repeated in any animal models, including human volunteers.
Can your genes protect you against COVID-19?
Several single nucleotide polymorphisms (SNPs) affect both the likelihood of a person getting infected with SARS-CoV and the severity of illness. These include human leukocyte antigen (HLA)-B*4601, which was associated with predisposition to infection and severity of illness among people in Taiwan and Hong Kong, and HLA-B*0703 (an allele found in around 3% of the general population), which also affected predisposition.3031
More recently, researchers looking at hospital staff at specific hospital in Taipei found that those with either a homozygous or a heterozygous Cw*0801 genotype were more than four times as likely (4.4 Odds Ratio) to contract SARS-CoV compared to those without this HLA genotype. The sample size was very small, but researchers calculated that the risk of infection was 3.3 for those heterozygous for HLA-Cw*0801 and 6 for homozygous individuals.32
The human leukocyte antigen (HLA) complex is an important determinant of susceptibility to infectious diseases. HLA class I genes are extremely polymorphic. This may well be because this enables rapid adaptation of the human species to a wide variety of pathogens. We don’t yet have data to suggest increased risk of COVID-19 with any particular HLA genotype, but there may be other ways your genes could affect your susceptibility to coronavirus.
For instance, another SNP, this time in FGL2, affected how much of the SARS-CoV virus a person shed in their nasopharynx (nose and throat) and how long their illness lasted, at least in people in Taiwan.3334 Other genes and SNPs of interested in SARS include those affecting interleukin-1-alpha and RelB, as well as CXCL10/IP-10 and heme oxygenase 1. These are all involved in modulating inflammation and immunity, which can affect clinical outcomes.35
Studies looking at SARS may offer clues about where to look for genes involved in COVID-19 susceptibility. Right now, of course, most researchers are focused on identifying and treating patients.
In addition, genes can affect your levels of ACE2. And, intriguingly, research suggests wide variation in the expression of ACE2 in lung cells.36 Across races and ethnicities, an average 0.64% of human lung cells expressed ACE2. In comparison, 2.5% of sample cells from Asian males expressed ACE2 versus 0.47% of cells from African and white samples. ACE2 expression was also higher in samples from males, but the data set was too small to do more than suggest an area to investigate further.
The Leeds Family Study also looked at ACE2 activity. Researchers concluded that up to 67% of the phenotype variation in circulation ACE2 depended on genetic factors. Specifically, ACE2 rs2106809 genotype CC or CT was associated with higher circulating ACE2 levels compared to the TT genotype.37
Other research looked at genes associated with ACE2 expression and found a wide variety of such genes, including those involved in carbohydrate metabolism and immune function. Such genes included: IDO1, IRAK3, NOS2, TNFSF10, OAS1, and MX1.38
We’ve only been living with and studying SARS-CoV-2 for a few months, so we still know very little about the genes or SNPs that might make us more vulnerable to COVID-19, more severe illness, or to passing it on to others. It may be fair, however, to consider the genes just mentioned, given the overlaps between SARS-CoV and SARS-CoV-2.
Is ACE2 the reason why women seem to fare better against COVID-19?
Interestingly, the gene encoding ACE2 is located on the X chromosome, and ACE2 expression is generally higher in females compared to males.39 This may explain in part why hypertension is more prevalent in males than females and why men seem to fare worse when they get COVID-19.
How so? Well, drawing on our discussion above, it seems that increased baseline ACE2 expression may slightly increase the risk of infection with coronavirus but higher levels of ACE2 may help prevent serious tissue damage once a person is infected.
In essence, the potential advantages and disadvantages of high or low ACE2 may depend on the phase on the disease.
So far, kids don’t seem to be all that susceptible to COVID-19. Why might this be?
SARS-CoV, MERS-CoV and SARS-CoV-2 all seem to affect children less frequently. Preliminary research suggests that kids might be just as likely to get infected with coronavirus but tend to have fewer of no symptoms compared to adults. Kids with coronavirus also seem to present with fever and then have gastrointestinal symptoms, compared with adults who may not have a fever and are more likely to develop breathing difficulties.40
All of this could mean that children are less likely to be tested for coronavirus than adults, which prompts the question: are children asymptomatic spreaders of coronavirus? Dispelling this idea, other research seems to show that all infants and most children infected with SARS-CoV-2 have been part of a family cluster outbreak where another family member contracted the virus first.414243
Why do kids fare better than adults at fighting off coronavirus? One answer could be related to levels of ACE2. Children aged 6 months to 17 years old generally have higher levels of ACE2 than adults.44 Higher levels of circulating ACE2 could help mop up coronavirus, preventing it from taking hold in any one tissue where it causes severe infection.
Researchers have also noted an increase in ACE2 in urine and plasma in mid to late pregnancy, as well as increased production and activity of ACE2 in the placenta and uterus.45 This may be to help enhance blood flow to the fetus and to support rapid growth but could have implications for susceptibility to coronavirus in pregnancy.
Looking ahead to future treatments for COVID-19
As well as scrambling to develop a SARS-CoV-2 vaccine and COVID-19 treatments, researchers are also eyeing up natural compounds as potential supports. Specifically, natural compounds that have previously been seen to influence ACE2.
For instance, catechin and curcumin (polyphenols in green tea and turmeric) bind both to the viral S protein and ACE2.46 As such, these compounds may be considered as having the potential to help prevent initial infection by tying up ACE2 receptors and binding to the virus itself. Their utility in people who already have COVID-19 may be limited, however. There is some evidence to suggest that curcumin could enhance expression of ACE2 in heart tissue.47 As it stands, far more research is needed before either of these compounds gets the green light for treating or preventing COVID-19. In the meantime, physical distancing, good hygiene, and taking steps to support good health all-round offer practical ways we can all keep the risk of COVID-19 low.