Wednesday, 28 August 2013

A perfect iFITm to fight viruses

There are an estimated 7 billion humans worldwide. That's 7,000,000,000, a huge number. However, 7 billion pales in comparison to the estimated 10 to the power 31 viruses living alongside us - that's 10,000,000,000,000,000,000,000,000,000,000. Put another way, for every predicted star in the universe there are 10 million viruses on Earth. Closer to home, within each of us there are approximately 4 trillion viruses; yet for the majority of our lives we will be healthy and free of viral disease. There are many reasons for this, not least because most viruses have no interest in humans. But another major factor is a set of cells and molecules to which we are deeply indebted: these are the components that make up our immune system.

The immune system can be broadly divided into two interlinked halves. There are the front line, rapid responders comprising the innate immune system; cells and molecules that are evolutionarily "designed" to react rapidly and broadly, controlling invasion from any foreign organism. The second half is the adaptive immune system. This has the big guns, taking longer to mobilize but with the power to fully clear invading organisms following the initial suppression from the innate system. Together these two halves co-ordinate a response that effectively removes almost all infectious agents we encounter. Every once in a while we will get briefly sick as the system kicks into full force, but largely, we will never notice the silent protection it provides. The halves are inseparable. However, without the rapid response of our innate system many viruses and other pathogens would be able to gain a foothold and potentially overwhelm us. Furthermore, the adaptive immune system cannot be triggered unless the innate system warns it of an invasion, making the innate immune system paramount for our survival.

Possibly the most important players in the innate response to viral infection are a group of proteins known as interferons (IFNs). Following an infection, IFNs trigger the expression of 200-300 genes, producing effector proteins that function as part of the innate immune response to block viral infection. It is known that these IFN stimulated genes protect us, however, very little is known about the function of individual proteins produced from these genes. In 2009 a major new component in the IFN response was discovered that is now known as InterFeron-Induced TransMembrane protein 3 (IFITM3). This protein was found through its ability to protect cells from influenza virus infection. Influenza virus, or flu, annually causes 3-5 million cases of clinical disease worldwide, and has the major potential for pandemic spread. It was subsequently found that IFITM3 is present in the cells of our lungs (the site of influenza infection) and that these cells can be stimulated to express even more of this protective protein following infection.
Influenza virus particles
Most importantly for the story of IFITM3, it was found not only to protect cells in a laboratory, but also to protect us on a regular basis. Usually flu is a minor illness, you simply get over it after a couple of weeks. However, certain people can be hospitalized, or worse. In a study of patients hospitalized by influenza, it has been found that a mutation in IFITM3 was over-represented. To put it another way, it seems that people who carry a mutation in IFITM3 are at an increased risk of severe flu infection.

What makes IFITM3, and its close relatives IFITM1 and IFITM2, even more exciting is that they don't just protect against influenza. At the time of writing, the list of viruses the IFITMs protect against is in double figures and includes some of the most notorious known to infect humans. Dengue virus, a mosquito borne virus that threatens around 3 billion people, is sensitive to IFITMs. Similarly, Ebola virus that can kill up to 90% of the people it infects is restricted by the IFITMs. HIV may even be kept in check by the IFITM proteins. This is to name but three. Obviously these viruses still cause infections and still kill on a daily basis. However, without protection provided by the IFITMs it is possible these viruses could be even greater killers.

Currently, we still do not completely understand how the IFITM proteins work. If this is fully elucidated we may be able to produce drugs that mimic their protective properties. Better yet, we may be able to regulate expression of the IFITMs or improve on their function and provide even greater levels of protection. Imagine if we could make a single drug that protected against infection by the four viruses already mentioned and a whole host of others! This may be slightly blue-sky thinking, but as someone at the start of a PhD in the field, that sky looks pretty bright and appealing to me. 

(NB. This article was entered into the Max Perutz Science Writing Competition run by the MRC by myself and is my own work in both cases)

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