Scientists find new way to target norovirus

15 January 2019

Interview with

David Bhella, University of Glasgow

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Now this time of year is notoriously bad for taking people out with various bugs and illnesses. And one of the worst offenders is norovirus. Every year millions of people succumb to norovirus infections, which lead to severe doses of D and V - diarrhoea and vomiting. The infection often also causes explosive outbreaks in schools, care homes and hospitals, and there are unfortunately no vaccines or drug treatments that can stop it yet. But now scientists at the University of Glasgow have discovered how this family of viruses completes a critical step that enables them to infect the cells in our intestines: contact with molecules on the cell surface triggers the virus to change the shape of its outer coat, creating a tube that connects the inside of the virus particle with the inside of the cell, allowing the viral genetic code to invade the cell. Chris Smith spoke with David Bhella from the study.

David - All viruses need to replicate inside ourselves. They can't grow by themselves so they want to gain access to ourselves and then turn the machinery of our cells into factories to produce more viruses. So we set out to understand how this family of viruses which includes norovirus can cross the cell membrane and enter our cells.

Chris - They’re excruciating small though these viruses aren't they.

David - Yes viruses are absolutely tiny. I think the thing I find amazing about viruses is they're actually smaller than the wavelength of light, to give you an idea of scale if you put 50000 viruses in a row, that row would be about the size of the full stop.

Chris - Which of course is a big challenge for you because you're trying to understand how this entity is infecting a cell but you can't see it, or can you? So how have you actually done the study?

David - So we used a technique called cryo-electron microscopy, electron microscopes use electrons which have a much smaller wavelength which allows it to see smaller things basically. Cryo-electron microscopy is a very powerful method, it's really emerged just the last few years as a technique that allows us to understand the shapes of biological molecules at the atomic level. So we can see the structure of the virus in terms of the atoms it is made of. And this gives us very powerful insights into how the virus does what it does.

Chris - So using that technique you can watch what the viruses do as they engage with the cell surface and then smuggle themselves inside. And that's enabled us to understand a bit more about the actual process, the nuts and bolts that are going on, when the virus particle does that.

David - Yes. So we wanted to understand the mechanism the viruses used to gain access to our cells. So for a virus to get into our cells it has to cross this cell membrane. So viruses are very tiny comparatively the cell is huge, and it's surrounded by this membrane which is like a fatty layer that the virus needs to try and cross. And it's like a brick wall. So viruses have evolved to bind onto molecules on the cell surface, we call the receptor. So the virus binds onto a receptor and then it tricks the cell to take the virus inside the cell through a process known as endocytosis and involves bringing things into a bubble or vesicle. So the virus can cross the cell membrane but it's still enwrapped in this vesicle called the endosome and the virus needs to break out of that. And it's a very difficult challenge for the virus to try and break through a membrane. So it's still basically outside the cell. It hasn't entered the cytoplasm of the cell.

Chris - I suppose it's a bit like if I partially inflated a balloon stuck my fingers in I'd end up with a finger inside the balloon but it's still got a layer of balloon around my finger. The problem for the virus is how do I get across that layer of rubber so that I'm really inside the cell. So how how have you attacked this and how do they do it?

David - We looked at the structure of the virus as it engages the receptor. And we did this by taking the virus and coating it in a fragment of the cell receptor that it binds to. And we discovered that it causes a large structural change in the virus. And we found this structural change results in the formation of a tube which likes to insert into membranes. So we think that this tube will provide a channel through which the virus can inject its genes into the cell where it can then begin to take over and turn that cell into a virus making factory.

Chris - So you've got this structure this tiny viral particle and it's basically protein which is its outer coat. And when it comes into contact inside this bubble with the receptor it likes to dock with, this forces that the virus proteins to rearrange themselves and change shape. And one group of them in particular forms this channel and that connects the inside of the virus particle to the inside of the cells so that's the portal through which the genetic information can flow.

David - Exactly right.

Chris - Does this mean then now you understand this a lot more that we know what we might have to go after if we're going to come up with an anti-norovirus drug?

David - What our study does is it provides another target in our attempts to devise methods for preventing norovirus disease. So we now understand the structure of this tube and have a good idea of what the mechanism will be that leads to genome release. So this gives us the insight necessary to try and devise tests that we could use to screen drugs to prevent that process and of course if you can stop the very first step of infection then you're going to stop the spread of virus. And that's a very powerful thing to try and go after.

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