In theory no virus or bacteria should be able to defeat the body's powerful immune system, but in practice this happens all the time. The bugs have evolved clever and intricate ways of turning off the immune response, allowing them to kill cells and cause illness.
Scientists working in the Department of Biochemistry and the National Pharmaceutical Biotechnology Centre at Trinity College Dublin have exposed one such ploy which enables the virus to block an important immune "switch".
The Trinity team was lead by Dr Andrew Bowie and was overseen by Prof Luke O'Neill, assistant professor of biochemistry and directory of biotechnology research. The work involved collaborating groups at the University of Oxford and the University of Sheffield. Their results were published late last month in the US Proceedings of the National Academy of Sciences.
"The project got underway because we were interested in a protein in the immune system called MyD88," Prof O'Neill explained. "This is a key switch in the immune system and we were interested in finding if there were more genes like MyD88."
MyD88 is central to the body's immune response to a virus, he said. It becomes activated when a cell is invaded by a virus and it triggers a cascade of 2,000 immune related proteins which come into play to destroy the invader.
The team relied on "bioinformatics", the use of massive stores of computerised information which catalogue the genetic sequences of genes. These catalogues are growing all the time as researchers worldwide sequence the genetic blueprint of all sorts of organisms, from fungi and bacteria to animals and humans. "Annotation" is the term applied to trying to understand the function of a gene using bioinformatics.
"We were searching the databases to find other versions of MyD88," Prof O'Neill explained. If you know the genetic signature of the gene, you can search for "homologues" in other species which will probably have a similar function.
The searches are automated and can take hours, but the team was amazed when they discovered a match to the human MyD88 protein resident in the pox virus. "The fact that we found it in a viral genome really caught our attention," Prof O'Neill said. "The question was what was the virus doing with a key switch in the human immune response."
The researchers soon had the answer. "What the virus seems to do is to make its own version of MyD88 and because it is subtly different than the human, it prevents the human MyD88 being turned on. It cunningly uses this protein to hijack the immune system."
The team discovered there were two viral genes, A46R and A52R, which encoded proteins which could subvert the MyD88 immune cascade. He likened MyD88 to a key cog in the immune machinery, but the viral protein swamps out the human version. "The viral MyD88 acts as an agonist and blocks its action," he said. "The virus makes a version of the cog that acts like a spanner in the works. This sort of mechanism has never been found before."
There are two immediate benefits which come from such a discovery, Prof O'Neill said. "It teaches us what the key control proteins are in our immune systems. It identifies a component of the immune system that is critical for a viral response. If you can soup-up that response you have a way to enhance what the immune system can do."
It also gives researchers a new target for pharmaceuticals that can interfere with the virus's own protection systems. The idea would be to use drugs capable of inhibiting the two viral genes, thus exposing the virus to the full powers of the immune response.
Prof O'Neill believes that many infectious agents succeed by interfering with MyD88. "We are actively searching for this in other viruses and have found a homologue in a bacterium."
The research was funded by the National Pharmaceutical Bio technology Centre at Trinity, the TCD arm of BioResearch Ireland. Further information on Prof O'Neill's research interests are available at http://www.tcd.ie/Biochemistry/LONeill.html and BioResearch Ireland's site is http://www.biores-irl.ie