The Evasive Tactics of the Schistosome parasite

20 March 2012

Interview with

Ed Farnell, Cambridge University

Chris - Parasites are organisms that live in or on another organism.  They steal nutrients to survive.  Nice!  But living inside a host species, as many of them do, comes with its own set of problems.  Parasites have to find ways to avoid the immune system and we now know that parts of the immune system whose job it is to get rid of parasites are the same parts that also cause allergies.  Dr. Edward Farnell from Cambridge University's pathology department works on this and he is with us.  So Ed, what does the immune system actually do to try to get rid of a parasite?  Let's start there.

Edward -   Yes, so parasites are very difficult for the immune system to deal with as other things, such as viruses and bacteria, are very small and the normal immune response to those is to send cells along which are actually capable of gobbling them up. They gobble them up, envelop them and then drop a load of chemicals on them and get rid of them.

Chris -   So that would be bacteria and viruses.

Edward -   Yeah, bacteria and viruses.  They're very small and the immune system can do that.  With parasites, certainly with the parasites we study, the worms, they're large and multicellular and there's no cell in your body that can come along and actually gobble it up.

Chris -   It would be like you trying to engulf a shark or a blue whale!

Edward -   Basically, yeah.  So, the body has developed a more recently evolved part of the immune system to fight parasites and instead of trying toSchistosoma worm envelop them, it sends along a specialised type of cell which, when it encounters the parasite and the parasite has been marked in a way that says "this is something to be destroyed by an antibody" these cells then release a lot of toxic chemicals onto the parasite which is hopefully what destroys the parasite.

Chris -   But it clearly doesn't work very well because if you look at the world population, a very high fraction, we're talking 10s of percent, are thought to be carrying parasites, especially worms, at any moment in time.  So these parasites are obviously pretty resourceful at getting around what the immune system has to throw at them.

Edward -   Yeah, they're very, very good at getting around what the immune system has to throw at them and it's done using a special antibody called IgE which recognizes special surface structures on the parasite.  But obviously, if it can't see these structures, if the IgE can't bind to those structures, then the cells can't release the chemicals and they can't destroy the parasites.  And so, the parasites have developed lots of very clever ways of avoiding that process.  So, the parasite I work on  is Schistosoma mansoni which causes the Schistosomiasis.  It's a huge problem.

Chris -   Bilharzia is the other name

Edward -   Yes and that actually has the adult worms which live in the bloodstream so they're exposed to the immune system all the time.  They see the immune system all the time.

They actually have a special outside layer called the tegument which wraps around them and actually hides the majority of the things that IgE can react against in the worms.  Then it takes in bits of your own blood and coats itself in your blood. Your body's immune system is also very good at not destroying yourself, and you tolerise to your own antigens when you're very, very small and so, the worms coat themselves in this to protect them.

Chris -   It's a massive game of subterfuge isn't it?  They're disguising themselves as you.  So, where are you in terms of understanding what this IgE is actually doing when it's going wrong? In other words, is there a way of stopping it going wrong so that it then can begin to re-attack the worm again because that's the answer to getting rid of the parasite, isn't it?

Edward -   Yes, so a lot of the work we look at is understanding which antigens the IgE is binding to and at what point the IgE, this antibody, actually sees them. So when another worm dies, a lot of the antigens which were previously hidden then become visible.  And then these are present in other stages of the lifecycle.  So for example, when the worm is invading through the skin, those may actually be present on the surface and then you raise a response then. So the more we understand about the infection of humans, the more we understand about how you defend against it.

Chris -   So does that mean, as someone lives with their parasite load, and these worms slowly die off of old age and then expose the various factors they had previously hidden, and you get this immune response, does that mean that the immune system does then get better over time at attacking them and eventually, does clear the parasite and is then protected?

Edward -   So we do see an age protection effect.  So the older people get, the more protected they become against the parasite and there's also various other things to do with the occupation and how much they're exposed to the parasite throughout their life.

Chris -   Okay, so if we can understand actually how it's doing this because one of the things it's doing is fiddling with this IgE system and IgE is very important with allergy because when it goes wrong, we get all kinds of allergies.  Does this mean then if you can work out how the parasite subverts that system, you could basically do the same trick in people who have too much IgE because they're allergic to things and deal with the allergy problem?

Edward -   Yes, certainly, what we're trying to do at the moment on the current projects I'm working on is we're really interested in what the IgE is actually binding to on the parasite, and what we think is actually the targets that you see, the allergens that you see, look like parasites to your immune system.  So that's why we're reacting against them.  So we're looking at the moment on all of the known allergen structures and we're seeing if we can actually find the examples of IgE binding to those in a parasitic infection.

Chris -   But what's intriguing is that if I have hay fever for example, which I do, I definitely get symptoms, but if I have a parasite, I don't necessarily get symptoms because of the parasite being there apart from the depleting effect it has and the debilitating effect it has on my body.  So there's obviously something else to it.

Edward -   Yeah, so there are factors that the parasites themselves also release which turn down the immune system and actually turn down the immune response, so some of our collaborators actually look at chemicals the parasite releases as it invades into the skin.  And what you actually find is that some of these molecules that are secreted as the parasite comes suppress the local immune response.  So you don't actually start to raise an immune response against that.  But then there's also another effect which you see within the whole population where people actually raise different immune responses to the parasites.  So genetic diversity means, some people respond to a parasite with a damaging reaction that looks very, very similar to severe allergy whereas other people actually, when they start to have very, very heavy parasitic burden start to turn down their immune system to stop themselves from hurting themselves.

Chris -   Do we know why?

Edward -   No, we don't.  There's almost certainly a genetic component to it and there's almost certainly an exposure component to it.  So it probably has a lot to do with when you were first parasitized, the state of your immune system as you're first parasitized, and then a whole host of other genetic factors which means that you may well produce what we call a modified response, whereby, you turn down your immune reactions which is beneficial to both you and the parasite.  I mean, that's what the parasite wants as well.  The parasites, they're very, very greedy.  They want you all to themselves.  They want to get in and stop other parasites from coming in and they also want to keep you as well as possible.  So we could consider that to be what must be the normal thought of response.

Chris -   Because this whole idea of the hygiene hypothesis where people who are infested with parasites have a lower risk of allergy.  Is that real and is there something really going on?  Is it that the parasite actively being in a person suppresses the immune response in this way or is it that the environment in which people acquire parasites makes people less likely to develop allergies overall?

Edward -   I think it's much more complicated than we used to think it was.  There have been several studies released that show that people are protected by having a worm parasite and the worm is doing something.  There is some cross reaction between their immune system. There are other studies that actually show or suggest that having a worm might not be so great for you or it may not actually suppress any allergy at all, and the key to understanding that is really understanding the similarity between the structures of allergens and the structures of the antigens that are being reacted against on the parasite by the immune system.

Chris -   So, how far away are you, do you think, from nailing this? So that we're in a position where we can say, "We understand what the parasite does to get around the immune response" and then we can turn the equation around and use this usefully to a.) Treat parasite problems and b.) Treat allergy problems?

Edward -   With the best will in the world, I'd like to say we're really, really close and we'd love to go up to say, yeah we can do this, but I think we need to understand a lot more about the interactions because they're really complicated.  The complex, but fascinating, interactions of how this happens.

Chris -   Thank you very much.  That's Ed Farnell.  He is from the Department of Pathology at Cambridge University.

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