Meningitis in Disguise
Chris - Professor Susan Lea has a paper in the journal Nature this week, explaining how the bacteria do this and manage to hide themselves. Susan, how do they disguise themselves?
Susan - Hi, Chris. Well the work came to us in a problem that was brought by Chris Tang at Imperial College. He'd been working with meningitis for many years, looking at the bacteria and trying to understand them in more detail, trying to generate therapeutics. They'd noticed a couple of years ago that the bacteria somehow managed to mark themselves as human cells by coating themselves in a protein that circulates in our own blood, called factor H. This protein is a very important part of how we regulate our own immune response in that we've got one arm of our immune system that essentially seeks to destroy anything it comes into contact with in the blood. To protect our cells we develop a series of sugars on our cells that then bind a protein called factor H which turns off this part of the immune system.
Chris - How do the Neisseria meningitidis bacteria exploit that?
Susan - Neisseria can't make the same sugars that we make. They don't have the machinery to make those sorts of chemicals. Instead the Neisseria has chosen a different route and manufactures another protein. Instead it uses this protein to essentially seek out and bind the factor H to coat the bacterium in factor H: the way our own cells have done but by using a very different chemistry underlying the reaction.
Chris - Your work has been to discover the structure of that protein to work out how the bacteria grab this protective, this disguise factor H from the blood and then decorate themselves with it?
Susan - Absolutely. We've worked with Chris to generate the structure of the actual complex between the proteins of the bacteria and the proteins from our cells. In doing this it allows us to see how the bacteria uses the chemistry of proteins to mimic the chemistry of sugars that we have on our cells. The interactions are actually very similar. Some years ago we looked at the structure of sugars binding factor H. We found the structure of this protein binding factor H mimics the same sorts of interactions that you use in protein-based chemistry rather than sugar-based chemistry.
Chris - And how, now that you've got that structure, will this help us to get a vaccine? We've had a vaccine for the A strain of meningitis for a long time and that's helped in places like Africa. We've had the vaccine for strain C which has made a dramatic difference for young people, especially people going to university. B has always been the big problem. 90% of meningitis cases in Britain are down to group B. How is this going to help us get a vaccine against this now?
Susan - Essentially the protein we've done the structure of is actually one of the components of the vaccines by both Novartis and Wyeth that are currently in phase through clinical trials are looking quite promising. We think, from looking at our structure, we predict that by altering a very small part of the protein we can make a protein that will no longer bind with factor H and we suspect that this will make a much better vaccine. It won't have a large part of its surface covered up my factor H. When you immunise somebody with the current versions of the vaccine trials that are going on - in fact much of the bacterial protein will be hidden from the immune system because it will be bound to factor H. You therefore won't get as good an immune response against it as you might otherwise get. We've made versions of this protein which are more than 98% - 99% identical to the natural form but they no longer can bind factor H. We think that these will be much better candidates for targets in the vaccine.