Understanding variants of the coronavirus can offer clues about the next threats

As the coronavirus spreads, it gains more opportunities to mutate in ways that make it easier to be transmitted from person to person. Knowing how the spike protein of the virus is changing is key to understanding how the virus works, according to a VCU expert who specializes in protein engineering.

Michael H. Peters, Ph.D.
Michael H. Peters, Ph.D., professor in the Department of Chemical and Life Science Engineering.

EDITOR'S NOTE: Peters' paper on SARS-CoV-2 variants now appears in "Microbiology Spectrum," the journal of the American Society for Microbiology. Access the article here

Scientists are closely watching the emergence of variants of the coronavirus that may be more infectious. The spread of troubling variants in different parts of the world, including in the U.S., is happening as officials are racing to inject vaccines into the arms of adult populations.

We spoke with Michael H. Peters, Ph.D., professor in the Department of Chemical and Life Science Engineering, about what scientists are learning about these variants, what could possibly be making them more dangerous and why vaccines are still a powerful weapon to fight COVID-19.

Why does the coronavirus have mutations and variants?

All viruses evolve over time. They’ve got some clever ways to try to evade our immune systems. For SARS-CoV2, the virus that causes COVID-19, we’re focusing on understanding the spike protein that densely decorates the surface of the virus that you see in pictures. A lot of the mutations and deletions are centered on the spike protein. We are trying to more fully understand how this protein functions.

What does the spike protein do?

The virus uses the spike protein to latch on to human epithelial cells (specifically to these ACE2 receptors) that line our lung airways and vasculature. The spike protein has different configurations. When the protein’s receptor binding domain is in its “up” position, the spike protein is more exposed and can probably latch on more easily to the body’s cells. But in the “down” position, it is enveloped down on itself and is not able to bind so readily. Why wouldn’t it be up all the time? This is an important question that scientists are working hard to answer.

Top view of the spike protein and rendition as it approaches a human epithelial cell. The blue segment is the part of the protein in the “up” conformation as it searches for the ACE2 receptor of its host. This segment tends to reach out farther in the variant state.

What can the body’s immune system do to defend itself?

Think of the virus as a burglar trying to get into your house. Our immune system takes pictures of this perpetrator and saves those pictures. That’s what happens when you’re exposed to the virus, or you get a vaccine. Our (memory) immune cells and antibodies carry around those pictures of the perpetrator. When that perpetrator invades your house again, an immune cell lines up that picture with the intruder and asks, “Is that the one?” What makes our immune system so effective is that our immune police officers take many pictures: not just one side of the spike protein but also from the back, and top, and other side. The good thing is that they don’t need a consensus to act, they just go into action. Some killer cells are like Clint Eastwood: If you’re marked, you’re dead.

What do we know about how the virus changes between its ‘up’ and ‘down’ modes?

We looked at how this virus stabilizes itself in an up state or down state. One of the critical questions is: What keeps it in the down state? The protein has specific internal binding points of attachment that create the different configurations. We energetically mapped the entire spike protein here at VCU looking for these “glue points” unique to the down state configuration. I was able to find a possible latch that helps to keep it down. We developed maps that identified those glue points.

How do those glue points relate to specific variants?

As far as variants go, these glue points obviously play a critical role. If there are mutations or deletions in those areas, that’s something we need to look at, to see how that changes the structure or function of this spike protein.

Way back in May, even before these latest variants, we had identified D614 as one of those key glue points that stabilize the virus in the down position. One of the variants of concern, called B.1.1.7. — which is spreading in the U.K. — has a mutation known as D614G. It’s what we call a “structure-breaking” mutation. When you see that, alarm bells and whistles go off — this could be a problem. You’ve just taken a glue point and you’ve put in a structure-breaking mutation. If you’ve unglued that point, the configuration may change. If the configuration changes enough, the immune system may not recognize the virus.

We looked at how that D614G changes the configuration. What does it do? The mutation puts the protein in an extended up state. Its arm, if you will, is a little bit longer and sticks out more. It can reach out and grab on a little easier. This is still all theoretical. It has to be proven that this is what’s causing increased transmission.

We looked at this other mutation called N501Y. It appears to give the spike protein a stronger ability to bind with cells in the body, like stickier fingers.

Both of these mutations, D614G and N501Y, are seen in another variant, B.1.351, which is spreading in South Africa. Our hypothesis is that it’s a double whammy — now this virus has a longer arm and stickier fingers. That may be leading to increased transmissions. Again, this still has to be proven.

How can a better understanding of variants help?

What we can do is start mapping sequences as they’re published against this glue-point map to see if there are any red flags. This is one way we could do a better job keeping up with the virus. If you find something that looks like it’s going to change configuration, we can dedicate our efforts to tracking that variant. You might want to reallocate resources and increase your sequencing efforts. We are in a race. We need to move as quickly as possible, gathering intelligence and planning attacks.

What do these variants mean for the currently approved vaccines — will they still work?

I’m not a virologist or an epidemiologist. But people should understand that it is critical to get vaccinated. It’s going to protect you from getting a severe case of COVID-19. These vaccines are out-of-the-park effective. It’s going to take a lot of variants and mutations to make them a lot less effective.