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Tuesday, 30 June 2015

Break the bug, spare the child. The partial attenuation of Small Hydrophobic (SH) gene deleted RSV is associated with elevated IL-1β responses.

Maurice Hilleman
Hero of the 20th Century
Many of our best (and oldest) vaccines are based upon a principle called live attenuation. This is where we have somehow modified the infectious agent so that it is less infectious, allowing the body to kill it and generate an immune memory in order to be fighting fit on exposure to the real thing. Historically, this process was achieved empirically (by trial and error), either by using an equivalent bug from a related animal for example – Cow Pox/ Small Pox. Alternatively the bugs can be serially passaged – grown in conditions that cause them to lose the genes that makes them infectious– e.g BCG/ TB . Or it can be done in a more targeted way, for example the live flu vaccine was developed by selection for growth at 32°C – closer to the temperature of the nose than the lung and therefore limiting infection to the nose causes colds at worst rather than lung infections. The master attenuator was a microbiologist working at Merck called Maurice Hilleman, who is probably the most influential person you have never heard of – saving more lives in the 20th century than any other person. I just want to emphasize his importance, because his record is often under stated, Hilleman invented 8 of the 14 vaccines we use today and yet, I had to google him to remind myself of his name.

However, we are now using more targeted approaches to attenuate viruses and bacteria. This is based on our improved understanding about how pathogens are able to infect people. For example what do they look for on the surface of cells to invade them, how do they coerce the machinery of the cell to make copies of themselves rather than more cells and critically how do they hide from the immune response. All human viruses have evolved ways of escaping the immune response (immune evasion), viruses that are not able to escape our immune response are not able to infect us – that’s why for example we don’t get myxamatosis from rabbits. In our recently published study in the Journal of Virology, we discovered a new immune evasion function for a gene in respiratory syncytial virus (RSV). RSV is a really important disease in children, causing 160,000 deaths worldwide and hospitalising 1% of all children under 1 in the UK (including my son).

The gene we were interested in is called SH (or small hydrophobic gene – sadly whilst drosophila geneticists get to call genes things like sonic the hedgehog and LUSH, we get names based on the structure or function, or sometimes just the order they were found). It is believed to make a small hydrophobic protein (can you see what we did there!) which folds up to make a pore or tube like structure. Based on other studies using similar proteins from other viruses, we hypothesized that this protein would actually alert the immune system, so we were surprised to find that infection with RSV lacking SH (RSV ΔSH) led to MORE of specific type of signal rather than less. We then saw that if this signal was blocked, the virus – which previously grew less well in lungs, grew to the same level as unchanged virus. We think this might be important both in our understanding about viral biology and possibly in developing strategies to make targeted vaccines. We were supported in this work by two grant programs from the EU, Aditec and Biovacsafe, which has enabled a lot of the work in the lab to be performed.

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