How the Coronavirus Attacks the Lungs -- and How We May Be Able to Stop the Damage

New research zooms in on the outer surface of the coronavirus to reveal more about how COVID-19 scars the lungs.
Two viruses

This colorized image of the coronavirus shows the outer edge of the virus, with the spike proteins in blue-green. Between those spikes are the envelope proteins that the new research explored.

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Brian Owens, Contributor

(Inside Science) -- One of the hallmarks of severe infection with SARS-CoV-2, the virus that causes COVID-19, is the damage it can do to the lungs, which can leave them scarred in a way that may cause long-term problems. Now, by studying the minute details of how the virus’s proteins interact with our cells, researchers have discovered how it causes that damage -- and suggested a way to develop drugs that will prevent it.

Qun Liu, a structural biologist at Brookhaven National Laboratory in New York, and his colleagues wanted to study how the virus attacks us at a cellular level. So they used a powerful imaging technique called cryo-electron microscopy to look at how one of the proteins that makes up SARS-CoV-2 interacts with our cells after infection. They focused on the envelope protein, called E for short -- one of the three proteins that makes up the virus’s outer surface, along with the membrane protein and the familiar spike protein that is the target of vaccines. They chose E because it had been largely neglected by other scientists. "People almost ignored this important protein because it’s not easy to work with," said Liu.

Liu’s team found that E serves two different functions for the virus. First, as one of the three surface proteins it has a structural role in holding the virus together. Without E, the virus would not be able to assemble new copies of itself. But it also has a secondary role: It helps the virus spread throughout the body in a way that leaves scarred and damaged lungs in its wake.

Once the virus uses its spike protein to bind to and enter a cell, E goes after a new target, the cell-junction proteins that keep the gaps between lung cells tightly closed. Using sophisticated imaging and 3D computer models, Liu showed that the small E protein fits neatly into a tiny pocket in a cell-junction protein within the lung, called PALS1, and pulls it out of place, disrupting the integrity of the lung’s surface. Once that happens our immune system tries to fix the damage, but sometimes overreacts, triggering the "cytokine storms" of immune proteins that can cause severe inflammation. And with the connections between cells weakened, it becomes easier for the viruses to escape from the lungs and travel through the bloodstream to infect other organs.

Liu said this work could help with the design of drugs that prevent the damage. "We provide a physical model people can use to figure out how to suppress the interaction between E and PALS1," he said. The work is published today in the journal Nature Communications.

Michel Fodje, a structural biologist at the Canadian Light Source in Saskatoon, said this work is important because it both helps us to understand how the virus propagates within cells and throughout the body, and it identifies a new target for drugs that could help prevent some of the damage caused by the virus. "E uses PALS1 to help the virus proliferate and multiply," he said. "By understanding how they bind, we can find a way to stop that process."

A drug that mimics E in some ways, for example, could compete with it for the binding sites on the lung's PALS1 proteins, taking up the space and crowding out the virus. Or other drugs could target E itself, destroying it or tying it up so that it can’t do its main job of forming part of the viral surface. "If we get rid of E, the virus will not be virulent; it can’t survive," said Liu.

The next step for Liu and his team is to look for interactions between E and other cell-junction proteins -- there is a whole family of them that do similar jobs in the lungs. "We’ll look for a common motif to see if we could develop common inhibitors," he said.

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Brian Owens is a freelance science journalist and editor based in St. Stephen, New Brunswick, Canada, where he writes for a variety of international publications.