Building barriers

27 May 2016

Interview with

Jim Collins, University of Texas Southwestern Medical Center

At the University of Texas Southwestern Medical Center, Jim Collins studies schistosomiasis, the worm behind the disease Bilharzia. A population of stem cells inside the worm is critical to maintaining the organism's outer coat, which, he put to Chris Smith, is how it fends off the immune system...

 Jim - Schistosomes infect 200 million worldwide, largely in sub-Saharan Africa. They kill about a quarter million of people every year. So, it's a serious problem. In fact, worldwide, it's almost as prevalent as diseases like malaria but receives far less attention.

Chris - How do people pick up the parasite in the first place?

Jim - People are exposed to the parasite when they go into water. People who were infected, they pass eggs through their urine or their faeces, and if that material reaches water, little critters come out which are called Miracidia that infect a snail. And then the snails inside the water, the parasites will propagate inside the snail and then they come out of the snail, and they're attracted by animals coming into the water namely humans. And then they burrow through your skin.

Chris - Once a person is carrying the parasite, where does it live in the body?

Jim - It depends on the schistosome. The schistosome we work on - Schistosoma mansoni - they live in the blood surrounding the intestine. That's where they start producing eggs. Once they're there, these parasites can live for an incredibly long period of time inside the blood. There's cases where people find that they move from endemic regions like Africa to places like the United Kingdom and they find 40 years later that they still have these parasites living inside them laying eggs.

Chris - But the blood must be a hostile environment for something to be able to persist with the full onslaught of the host's immune system potentially at its doorstep. How does it do that?

Jim - It's an open question. That's what this paper really tries to get at. What we knew is the parasites are capable of surviving inside the blood for decades. And so, we previously showed that they have these stem cells: basically cells that are able to rejuvenate tissues that are getting old. What we found in this paper was that the main job of these stem cells in these parasites is to generate the parasite's skin. This really unique structure, called the tegument. The tegument is what actually interfaces with the host immune system. It's not really known what features of the tegument allow the parasite to be able to invade the immune system. What we find is that the stem cells are continuously making new tegumental tissue. And so we think this doesn't necessarily answer the whole question about how the parasites are able to invade the host immune system, but we really think this is a very important clue as to what sorts of developmental tricks the parasite is using to be able to survive in the host blood.

Chris - And therefore, if one shuts down those stem cells, do you see a corresponding reduction in the production of this tegument and therefore a reduction in longevity or ability to fend off the host immune system in those worms?

Jim - Yes, we get rid of the stem cells - so we can kill the stem cells - and we completely blunt the ability to make new tegumental cells. But we don't know whether that has a consequence in the context of a natural infection. So these experiments that we do, we do them in a dish without a host immune system there.

Chris - How did you manage to show at this stage that those stem cells are producing that particular layer?

Jim - What we were able to do in the parasite is, we can kill these stem cells quite efficiently using genetic techniques, or also by just simply irradiating the parasites and that will kill all the stem cells. When we looked at the genes that were affected when the parasites didn't have stem cells for a really long time, we found that a number of these genes were genes previously shown to be associated with the schistosome's tegument. And so, that was a really big clue for us. So then what we did is we used a methodology to label the stem cells and ask, "what do they become?" It turns out what we were able to find is that a large fraction of the stem cells end up giving rise to cells that express things that are known to be associated with the tegument.

Chris - Is there particularly high turnover of these cells which would tell you that, in turn, there must be a very high turnover of the tegument - the skin of the parasite - which you could therefore deduce is because it is fending off actively some kind of host attack?

Jim - Exactly. So when we killed the stem cells, within a few days we lose progenitor cells to the tegument. And so, what we think is that stem cells are rejuvenating this tegumental tissue at a very high rate. The tegumental tissue is kind of a short-lived sort of surface.

Chris - So, does this give us some insights into how we might be able to attack schistosome in a new way? Is there a way of getting at those cells and effectively rendering it susceptible because it can't maintain this very high turnover of its outer layer?

Jim - Yeah. So there's two things. If we blunt the ability of the parasite to have stem cells that proliferate, that will ultimately lead to death of the parasite inside the host. The other real opportunity - the best thing for us - in treating schistosomiasis wouldn't necessarily be a drug but would be a vaccine. When we look at our data set, we basically have stumbled into a treasure trove of potential anti-schistosome vaccine candidates. In fact, some of the candidates that are being developed now as anti-schistosome vaccines are on the lists of genes that we identified. And so now we have potentially hundreds of molecules that we can follow up on or somebody else can follow up on to try to develop the next generation of anti-schistosome vaccines.

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