Curing the common cold

23 September 2019

Interview with 

Ian Goodfellow, University of Cambridge


A woman blowing her nose


Most of us succumb to an average of 3 coughs and colds per year. The main culprit in over half of cases are viruses called rhinoviruses and enteroviruses. When a symptomatic person sneezes, they spray out a mist of millions of these particles that drift about in the air waiting for you to breathe them in. Once they settle on the cells in your nose and throat, they invade, hijack the cells and transform them into virus factories; and then cycle starts all over again, making you feel awful in the process. But in a new study in the journal Nature Microbiology, Jan Carette and his team at Stanford University have identified a protein in our cells that these viruses rely on when they grow. And cutting off the supply of this substance halts the viruses in their tracks. So could this potentially pave the way for a cure for the common cold? Cambridge University virologist Ian Goodfellow took me through the results of the new study…

Ian - In this paper they've essentially identified a host protein that appears to be essential for a number of viruses that cause the common cold and enteric infections. When they’ve deleted this gene encoding this particular protein, the viruses are no longer able to infect cells.

Chris - How did they find the gene in question?

Ian - To identify the gene, they used a process to delete every single gene in human DNA.

Chris - Is that what, one by one? So they go through the entire genome, and one at a time disable one gene after another, and then test whether or not that disabled gene has an effect on the virus?

Ian - Exactly that. So you mutate every single gene one by one, then you infect them with the virus, and then you look for cells that survived. And these cells that survived are resistant to infection, and therefore have a mutation in a gene that is essential for the virus life cycle.

Chris - Right. So they identified a gene. What is that gene that they've found that seems to be so important, and do they know why disabling it has this effect on the virus?

Ian - The gene itself was called SETD3, it's a protein known as a methyltransferase. And they don't know exactly what stage in the virus life cycle it plays its role, but they know that in the absence of this protein the cells are largely completely resistant to infection.

Chris - They show that in the dish to start with, but would that work in a living animal? Because it's one thing to disable a gene and have a cell still thrive in a dish, but very different with a whole animal in which you are trying to do this.

Ian - This is one of the beauties of this particular publication. They've translated their observations from immortalised cells into a whole organism model. So they've taken a mouse model and they've inactivated this gene, and shown that when you infect these mice with these various viruses, they're completely resistant to infection.

Chris - And clinically, what's the relevance or use of this discovery? How could virologists now take this forward, and is it potentially a doorway towards - I hate the phrase - but a cure for the common cold, or at least some forms of the common cold?

Ian - So what this paper does is it really identifies a key whole-cell protein that's important for a whole group of viruses that cause a range of diseases. It isn't immediately like tomorrow we can all of a sudden develop a drug to this particular protein, but what it does is it says, if we find a way to modify the function of this protein then we probably have an effective way of treating, or controlling, or preventing the infection by these viruses. So it identifies SETD3 as an essential component in the virus life cycle. And if you can make drugs that target SETD3 you might be able to inhibit the virus replication.

Chris - Could the same strategy be used for other clinically relevant infections? Because colds are one thing, they're a nuisance, but they're not by any means the main way in which viruses bring down the human race.

Ian - Yes, exactly, and it's become increasingly common in virology now for individuals to use this precise approach, where you use CRISPR-Cas screening to identify host proteins that are essential in a virus life cycle, and then to use that as a potential target for therapeutic approaches. And just recently we've undertaken some work on a related family of viruses known as noroviruses - that cause gastroenteritis - to do precisely the same type of approach. And when we've done that we've done a CRISPR-Cas screen to identify a single protein known as G3BP1. This protein is absolutely essential for both the mouse norovirus replication and for human norovirus replication. And we hope that in the future this will enable us to develop a potential therapeutic approach for the control of norovirus-induced gastroenteritis.

Chris - Viruses are notorious for being able to change their genetic makeup; they mutate or change. If we did work out how to use these vulnerabilities, to make drugs to block them, is there not a high likelihood that pretty quickly, the viruses would fight back by just adjusting their modus operandi to bypass whatever block we put in the way?

Ian - This point about the development of resistance to drugs is a real key factor when we consider developing any sort of therapy for viruses. And as you say, viruses change very rapidly. But when we target a host protein it's very, very difficult for the virus to change to overcome that. It's not impossible, but it's much easier for a virus to develop resistance to drugs that target viral proteins than it is for it to develop resistance against drugs that target the host.


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