Meet ACE2, the Enzyme at the Center of the Covid-19 Mystery – WIRED

Posted: June 4, 2020 at 2:47 pm

During the first chaotic months of the Covid-19 pandemic, it was already clear that the novel coronavirus spreading around the world didnt 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. Its a key cog in a biochemical pathway that regulates blood pressure, wound healing, and inflammation. ACE2s 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 isnt the only thing that fits in ACE2s 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 cells 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 someones cells, the higher the persons risk. Thats the hypothesis Sheltzer and Smith were interested in investigating. They werent 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 arent any simplistic, reductionist explanations that can unify all the clinical data thats been recovered so far, says Sheltzer. Instead, a more complicated picture has emerged. But its one that still has ACE2 at the center of the action.

Smoking Dials Up the ACE2

Sheltzer and Smith, confined to their home, couldnt 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 couldnt find any differences between young adults and older ones. Aging didnt 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.

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Meet ACE2, the Enzyme at the Center of the Covid-19 Mystery - WIRED

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