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Knowing me, knowing flu

by Guest Author on 13 Dec 2012

Sarah Smith

Sarah Smith

Why are some people more vulnerable to flu than others? Sarah Smith, a PhD student at the Wellcome Trust Sanger Institute, describes one reason why in her shortlisted article for the Max Perutz Science Writing Award 2012.

You’re 100 feet below sea level, crammed onto a London tube full of commuters, all breathing in the same stale air. The tickle in your nose is becoming too hard to ignore, but where’s a tissue when you need it? Aaaachhhhhhooo! Oops. You just sent 20,000 salivary droplets hurtling across the carriage. If you’re infected with influenza there could be thousands of viral particles in that sneeze. If everyone in your carriage inhaled a few of these particles, the outcome could be dramatically different for each person. Why? That is where my research matters.

After a virus infects a person, the severity of the disease that develops is influenced by both the virus and human genes. A gene is a sequence of DNA nucleotides (A, T, G or C) that provides the instructions for a cell or virus to assemble a protein, the bricks and mortar of the cell.

Both humans and viruses have been evolving together over time in a sort of arms race, one gaining a small advantage over the other, and then the other hurrying to catch up. This notion was inadvertently but eloquently described by the Red Queen in Lewis Carroll’s novel Alice in Wonderland, ‘It takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast’.

My research aims to understand the tools our body uses to fight off viral infections, and to identify how the virus makes small changes to its genes to evade the human immune system. Although influenza causes mild symptoms in most people, it can be lethal to some. It also has an enormous economic impact; the estimated financial burden of influenza epidemics in the United States alone amounts to $87.1 billion each year.

In the first few hours after an influenza infection, the sentinel cells patrolling the human body detect the invading influenza virus and release an important chemical called interferon. Release of interferon is a warning signal detected by receptors on neighbouring human cells that causes hundreds of anti-viral genes to switch on. I am studying one of these genes: IFITM3.

During a preliminary experiment, I increased the amount of IFITM3 protein in cells and the degree of infection by influenza was dramatically reduced. We then discovered that mice missing this protein became very sick when infected by influenza, whereas those with the protein recovered quickly.

My supervisor and I started to wonder whether people who became very ill after an influenza infection had any differences in their IFITM3 gene compared to the general population, possibly accounting for their severe responses. To test this idea, DNA was collected from the blood samples of 53 people who were hospitalised with a confirmed influenza infection during the 2009 pandemic. When I read the sequence of the IFITM3 gene in these patients I found that overall they were more likely than an ‘average’ European to have a one nucleotide change in this gene. Now, you may be wondering, how much damage can be caused by one out of 399 nucleotides being altered? Well, potentially, quite a lot.

We realised that this one change could alter the plans enough for the cell to build a shorter, trimmed protein. Think of it like a switch rail on a railway track that can be moved to determine the direction of the train: when a ‘T’ is substituted for a ‘C’ it could cause the machinery the cell uses to assemble the protein to ‘derail’ early, making a shorter protein.

We tested this theory back in the lab by engineering cells to make the cropped version of this protein, which we predicted would be present in these patients. We infected these engineered cells with influenza virus, alongside cells producing full-length IFITM3 protein. The results showed that 60 per cent of the cells expressing the cropped protein were infected compared to only 1 per cent of the cells expressing the full-length version. This suggests that the region of the IFITM3 protein that prevents influenza infection may have been lost in the cropped protein.

Great! So why does my research matter? Well, at the moment people are prioritised for influenza vaccinations if they are ‘at-risk’, such as asthmatics or the over 60s. Knowing your IFITM3 variants could also inform this kind of vaccination programme, along with other important genes we discover. Furthermore, influenza can swap and change its genes and chromosomes easily with other viruses, which allows the emergence of more virulent strains that can lead to pandemics. Ultimately, by improving our understanding of how influenza interacts with human cells we can improve not only the vaccines we design, but the treatments we provide.

Sarah Smith 


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