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Thursday, August 13, 2020

Explained: How ‘corona’ of the virus changes into a hairpin shape — and why

Freeze frames of SARS-CoV-2 spike protein show dramatic change of shape after it fuses with a human cell. Scientists suggest it may help distract our immune system; findings may matter in vaccine development

Written by Kabir Firaque | New Delhi | Updated: July 25, 2020 9:48:51 am
Structure of SARS-CoV-2, including the spike protein. (Source: Wikipedia)

The spike protein of SARS-CoV-2 — the ‘corona’ in the coronavirus that causes Covid-19 disease — has just revealed new secrets. Researchers have found that the spike protein changes its form after it attaches itself to a human cell, folding in on itself and assuming a rigid hairpin shape. The researchers have published their findings in the journal Science, and believe the knowledge can help in vaccine development.

What is the spike protein?

It is a protein that protrudes from the surface of a coronavirus, like the spikes of a crown or corona — hence the name ‘coronavirus’. In the SARS-CoV-2 coronavirus, it is the spike protein that initiates the process of infection in a human cell. It attaches itself to a human enzyme, called the ACE2 receptor, before going on to enter the cell and make multiple copies of itself.

What has the new research found?

Using the technique of cryogenic electron microscopy (cryo-EM), Dr Bing Chen and colleagues at Boston Children’s Hospital have freeze-framed the spike protein in both its shapes — before and after fusion with the cell.

Cryo-EM images of SARS-CoV-2 before and after fusion with the human cell. Postfusion shape is like a rigid hairpin. (Source: Provided by Dr Bing, Chen, Boston Children’s Hospital)

The images show a dramatic change to the hairpin shape after the spike protein binds with the ACE2 receptor. In fact, the researchers found that the “after” shape can also show itself before fusion — without the virus binding to a cell at all. The spike can go into its alternative form prematurely.

What does that signify?

Dr Chen suggests that assuming the alternative shape may help keep SARS-CoV-2 from breaking down. Studies have shown that the virus remains viable on various surfaces for various periods of time. Chen suggests that the rigid shape may explain this.

More significantly, the researchers speculate that the postfusion form may also protect SARS-CoV-2 from our immune system.

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In what way can it protect the virus from the immune system?

The postfusion shape could induce antibodies that do not neutralise the virus. In effect, the spikes in this form may act as decoys that distract the immune system.

“Antibodies specifically targeting the postfusion state would not be able to block membrane fusion (viral entry) since it would be too late in the process. This is well established in the field of other viruses, such as HIV,” Chen told The Indian Express, by email.

In principle, if both conformations shared neutralising epitopes (the part of the virus targeted by antibodies), then the postfusion form too could induce neutralising antibodies, Chen said. “But because the two structures are often very different, in particular, in case of SARS-CoV-2 and HIV, I think it is not very likely that the postfusion form would be useful as an immunogen,” he explained.

Do the two forms share any similarities?

Yes, both the “before” and “after” forms have sugar molecules, called glycans, at evenly spaced locations on their surface. Glycans are another feature that helps the virus avoid immune detection.

How is the knowledge about the alternative shape useful?

The researchers believe the findings have implications for vaccine development. Many vaccines that are currently in development use the spike protein to stimulate the immune system. But these may have varying mixes of the prefusion and postfusion forms, Chen said. And that may limit their protective efficacy.

Chen stressed the need for stabilising the spike protein in its prefusion structure in order to block the conformational changes that lead to the postfusion state. If the protein is not stable, antibodies may be induced but they will be less effective in terms of blocking the virus, he said.

“Using our prefusion structure as a guide, we should be able to do better (introducing stabilizing mutations) to mimic the prefusion state, which could be more effective in eliciting neutralizing antibody responses,” Chen told The Indian Express. “We are in the process of doing this in case the first round of vaccines are not as effective as we all hope.”

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