During the first chaotic months of the Covid-19 pandemic, it was already clear that the novel coronavirus spreading around the world didn’t affect everyone equally. The earliest clinical data out of China showed that some people consistently fared worse than others, notably men, the elderly, and smokers. It made some scientists wonder: What if the elevated risk of severe infection and death shared by these different people all boils down to differences in a single protein?
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Jason Sheltzer, a molecular biologist at Cold Spring Harbor Laboratory, started talking about this possibility with his partner, Joan Smith, a software engineer at Google, during the early days of their New York lockdown. “We thought maybe the simplest explanation could be if all these factors affected the expression of ACE2,” says Sheltzer.
ACE2, which stands for angiotensin-converting enzyme 2, is a protein that sits on the surface of many types of cells in the human body, including in the heart, gut, lungs, and inside the nose. It’s a key cog in a biochemical pathway that regulates blood pressure, wound healing, and inflammation. ACE2’s amino acids form a grooved pocket, allowing it to snag and chop up a destructive protein called angiotensin II, which drives up blood pressure and damages tissues. But angiotensin II isn’t the only thing that fits in ACE2’s pocket. So does the tip of the mace-like spike proteins that project from SARS-CoV-2, the coronavirus that causes Covid-19. Like a key turning in a latch, the virus gains entry to the cell through ACE2, then hijacks the cell’s protein-making machinery to make copies of itself. An infection begins.
In the early days of the pandemic, the thinking went something like this: The more ACE2 a person has, the easier it should be for the coronavirus to invade and advance through their tissues, causing more severe forms of the disease. The more ways inside someone’s cells, the higher the person’s risk. That’s the hypothesis Sheltzer and Smith were interested in investigating. They weren’t alone. As the virus spread beyond China, other high-risk groups surfaced: people with heart conditions, high blood pressure, diabetes, and obesity. Many people in these groups take medications that are known to boost ACE2 expression. So again, scientists wondered, could that protein be responsible?
But as researchers began to probe the relationship between ACE2 and this dangerous new disease, the data refused to line up in any neat, predictable patterns. “What we know now is that there aren’t any simplistic, reductionist explanations that can unify all the clinical data that’s been recovered so far,” says Sheltzer. Instead, a more complicated picture has emerged. But it’s one that still has ACE2 at the center of the action.
Smoking Dials Up the ACE2
Sheltzer and Smith, confined to their home, couldn’t run any experiments to tease out their initial hypothesis. Instead, they combed through existing data sets from both animal and human studies that measured the level of gene expression in various tissues. Over and over, they found that women and men produced similar amounts of ACE2 inside their lung cells. They also couldn’t find any differences between young adults and older ones. Aging didn’t change ACE2 one way or another. But the smokers were a different story.
When they looked at gene expression inside the lungs of smokers versus nonsmokers, they saw a huge spike in ACE2 coming from one particular kind of cell: secretory goblet cells. The job of these mucous-makers is to coat the inside of the respiratory tract, protecting it from any irritants you might breathe in (like say, tar, nicotine, or any of the other 250 harmful chemicals in cigarette smoke). The more people smoked, the more their goblet cells multiplied in an effort to trap these chemicals before they could damage surrounding tissue. Those expanding goblet cell army ranks fueled a surge in ACE2, as Sheltzer and his coauthors described in a study published in Developmental Cell in mid-May.
“Our analysis suggests a partial explanation for the link between smoking and the coronavirus,” says Sheltzer. Another study, conducted at the University of British Columbia, published two days earlier also found that the cells of smokers and those with chronic obstructive pulmonary disease, or COPD, produced more ACE2.
To really understand if that link is causative though, will take more time and lab experiments. Scheltzer’s team is just getting started with those—growing lung cells in dishes, bathing some of them in cigarette smoke inside an enclosed chamber, and then adding live SARS-CoV-2 to see if the smoke-exposed cells produce more ACE2 and are more likely to get infected than the smoke-free cells.
Drugs Can Alter ACE2, Too
Because SARS-CoV-2 primarily attacks the lungs, doctors and scientists expected people with asthma to also be among the most vulnerable to Covid-19. But data out of China and New York indicates that asthma patients make up just a very small fraction of people hospitalized with Covid-19. “No one really knows why that is,” says Michael Peters, a pulmonologist at UC San Francisco. For the past seven years, he and his colleagues at six other clinical research centers have been studying a group of 400 asthma patients, trying to understand the biological mechanisms behind how the disease develops and progresses in different people.
In a study published in April in the American Journal of Respiratory and Critical Care Medicine, the researchers looked at how much ACE2 their patients were producing in their lungs’ immune cells. While they didn’t see much difference between asthma patients and healthy people, they did find that asthma patients who used steroid inhalers had noticeably less ACE2. In general, steroids tamp down inflammation, and early on doctors in China used them to treat serious cases of Covid-19. “Our data suggests inhaled corticosteroids might be one reason why asthma hasn’t emerged as a big risk factor for Covid-19,” says Peters. “But it’s still really unclear if that’s the only thing going on.”
In other words, asthma patients might be biologically more vulnerable, but in practice they could be protected by steroid treatments that knock down ACE2 production. And inhalers aren’t the only drugs that can modify ACE2 expression. During the early days of the outbreak, some researchers noticed that many Covid-19 patients had high blood pressure, and to lower it, were taking two classes of medications known to increase levels of ACE2. That idea prompted doctors around the world in March to warn the millions of people taking these drugs—angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)—of a potential increased risk of catching Covid-19.
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That hypothesis has since collapsed. A series of large epidemiological studies looking at Covid-19 patients on these drugs found them to be harmless. At least a dozen medical societies and associations, including the American College of Physicians and the American Heart Association, issued statements saying that people taking antihypertensive medications should continue to do so. “The fear was that in the same way people have been self-medicating with things like hydroxychloroquine, they would start to self-de-medicate, which could be equally disastrous,” says Paul Insel, a molecular pharmacologist at UC San Diego, who has coauthored a forthcoming review of the risks of ACEIs and ARBs to Covid-19 patients.
He says it would be a mistake for people to try to lower their levels of ACE2. Without it, the hormone angiotensin II builds up, which not only raises blood pressure but also can trigger dangerous storms of inflammatory molecules and cause tissue damage. And it would probably be futile, since the coronavirus doesn’t need that many molecular doors; scientists estimate it only takes a few thousand SARS-CoV-2 particles to establish an infection.
Striking the ACE2 Balance
In fact, scientists like Insel are beginning to suspect that some of the more severe Covid-19 symptoms may actually be caused by not having enough ACE2. When the virus binds to the receptor, it clogs it up so it can’t do its regular job. Additionally, the cell responds to this attack by sending out a different enzyme to shear all the remaining ACE2 receptors off its surface. That leaves those tissues with no way to put the brakes on runaway inflammation, leading to more cell death.
“That’s the double-edged sword,” says Gavin Oudit, a cardiologist and the director of the Heart Function Clinic at the University of Alberta, who studies the ACE2 signalling pathway. “ACE2 is a very protective molecule. That’s what makes this new coronavirus so deadly—because it evolved to bind to this molecule that you need to have a functioning heart, lungs, and other organs. What this virus does is get rid of ACE2 from where you need it.”
What’s important, explains Insel, is striking the right balance. “It’s kind of a yin-yang relationship,” he says. “Is there a sweet spot? That’s what we’re hoping.”
That’s why researchers have now begun clinical trials to test whether widely prescribed blood pressure drugs, which either neutralize angiotensin II or halt its production altogether, might actually control and treat the disease caused by SARS-CoV-2. Insel’s colleague, Rohit Loomba, is currently enrolling patients in one such trial at UCSD. Many other drugs now in testing work by gunking up viral replication, like remdesivir and favipiravir. Other strategies involve blocking the virus from attaching to ACE2 in the first place, either with antibodies from survivors, artificial antibodies, or a vaccine. Blood pressure drugs wouldn’t target the virus at all. Rather, they’d try to correct a molecular imbalance made worse by the viral infection.
“We’re talking about understanding how the disease plays out. How does it progress at the level of tissues and cells?” asks Insel. “If we could stop that, then we could stop these more serious infections.”
It’ll be months before these clinical trials yield results. So while ACE2’s role in the start of an infection may be clear, there’s still a lot left to learn about how the molecule influences the course of the disease that follows. Still, that scientists know this much already is remarkable, says Peters, the UCSF pulmonologist. “We don’t really understand how viral receptor expression influences susceptibility to most diseases,” he says. The technology required, like being able to peer inside a single cell and see what proteins it’s making compared to its neighbors, has only evolved in the last few years. “We’re at the cusp of being able to do it,” he says. “I’d bet that we’ll get there for this disease probably within the next decade.”
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