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DEPARTEMENT DES RELATIONS EXTERIEURES, Communication Recherche Université libre de Bruxelles Aéropole – Avenue Lemaître 19 – B-6041 Charleroi NATHALIE GOBBE, TEL. : [phone] OU [phone] –E MAIL : [e-mail] NANCY DATH, TEL. : [phone] – E MAIL : [e-mail] Communiqué de presse Charleoi, le27 août 207 ULB-IBMM, Laboratoire de Parasitologie moléculaire, Professeur Pays : NewScientist.com publie une synthèse de leurs recherches sur la maladie du sommeil Chaque année, plus de 300.000 personnes meurent de la maladie du sommeil africaine. Ravageuse, la maladie est causée par un parasite, le trypanosome, que transmet la mouche tsétsé. Particularité : ce parasite change constamment d’apparence de sorte qu’il reste aujourd’hui inaccessible aux anticorps. Depuis les années ’90, le professeur Etienne Pays et son Laboratoire de Parasitologie moléculaire (IBMM) à l’ULB étudient le trypanosome. Leurs découvertes ont déjà permis d’importantes avancées, ouvrant dernièrement la voie à un médicament contre la maladie du sommeil africaine. Dans son édition du 22 août, la revue NewScientist.com publie une synthèse des recherches prometteuses du laboratoire de l’IBMM, Institut de biologie et de médecine moléculaires : article ci-dessous. Pour toute interview du professeur Pays, contactez : Prof. Etienne Pays, 00 32 (0)71 37 87 59 (secrétariat 00 32 (0)71 37 87 51), ...

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D EPARTEMENT DES RELATIONS EXTERIEURES ,Communication Recherche Université libre de Bruxelles Aéropole – Avenue Lemaître 19 – B-6041 Charleroi N ATHALIE GOBBE ,T EL . :[phone] OU [phone]–E MAIL : [e-mail] N ANCY D ATH ,T EL . :[phone]–E MAIL :[e-mail]

Communiqué de presse  Charleroi,le 27 août 2007 ULB-IBMM, Laboratoire de Parasitologie moléculaire, Professeur Pays : NewScientist.com publie une synthèse de leurs recherches sur la maladie du sommeil Chaque année, plus de 300.000 personnes meurent de la maladie du sommeil africaine. Ravageuse, la maladie est causée par un parasite, le trypanosome, que transmet la mouche tsétsé. Particularité : ce parasite change constamment d’apparence de sorte qu’il reste aujourd’hui inaccessible aux anticorps. Depuis les années ’90, le professeur Etienne Pays et son Laboratoire de Parasitologie moléculaire (IBMM) à l’ULB étudient le trypanosome. Leurs découvertes ont déjà permis d’importantes avancées, ouvrant dernièrement la voie à un médicament contre la maladie du sommeil africaine. Dans son édition du 22 août, la revueNewScientist.compublie une synthèse des recherches prometteuses du laboratoire de l’IBMM, Institut de biologie et de médecine moléculaires : article ci-dessous. Pour toute interview du professeur Pays, contactez : Prof. Etienne Pays, 00 32 (0)71 37 87 59 (secrétariat 00 32 (0)71 37 87 51), [e-mail]

Cholesterol: Secret of our killer blood

22 August 2007 NewScientist.com news service Henry Nicholls

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Web Links WHO page on African trypanosomiasis Programme on African trypanosomiasis Medicin sans frontieres

A FLY lands on your arm, swivels its head and raises its forelimbs to clean its long, blood-sucking proboscis. It gives you a nasty bite, but this is the least of your worries. It is the army of microscopic parasites injected into your bloodstream that you really need to be concerned about.

For this is no ordinary fly. It's a tsetse fly, the carrier of the single-celled parasites that cause sleeping sickness. First, you notice aching joints and a headache, then a fever. Then you become confused and your sleep cycle goes awry. Without treatment, you will die, yet the only drug that can help at this late stage is so dangerous that there's a 1 in 20 chance it will kill you.

The trypanosome parasites that cause African sleeping sickness are awesome adversaries. They continually change their coats, eluding our immune system and making it virtually impossible to develop a conventional vaccine. Yet it has long been clear that our bodies have evolved a very effective defence against almost all trypanosomes. Of the dozens of strains that infect livestock and other mammals, just three can infect humans. Somehow, our bodies fight the others off.

Now at last researchers have not only discovered the secret of our natural defence against trypanosomes, they have also worked out how the most deadly trypanosome manages to dodge it. The findings have already led to a potential treatment that promises to wipe out this parasite with few if any side effects.

Since the 1970s, biologists have known that our ability to fight off most strains of trypanosomes has something to do with "good cholesterol", or high-density lipoprotein. Particles of HDL are complex bundles of fats and proteins that carry cholesterol to the liver for recycling.

Only recently have researchers managed to sift through HDL's long list of ingredients and identify those responsible for killing trypanosomes, says Etienne Pays of the Free University of Brussels (ULB) in Belgium. The spotlight has landed on two minor players in the HDL complex - haptoglobin-related protein (Hpr) and apolipoprotein L-1 (ApoL-1). There is now strong evidence, says Pays, that while Hpr helps HDL get into the parasite, ApoL-1 actually does the damage.

When the parasite engulfs HDL particles, they end up in the cellular equivalent of the stomach: little sacs called lysosomes that are full of digestive enzymes. As the HDL particles break up, the freed ApoL-1 enters the lysosome membrane and effectively creates holes in it. "We think that ApoL-1 triggers an influx of chloride ions from the cytoplasm," says Pays. The rising concentration of chloride makes more water flow

into the lysosome, causing it to swell and swell. Within hours, the long thin trypanosomes turn into bloated balls and die.

There is still some disagreement over the precise role of Hpr in all this, says Jayne Raper of the New York University Medical Center in Manhattan, but ApoL-1 seems to be the main player. In recent experiments, her team created genetically engineered mice that made Hpr only, ApoL-1 only, or both Hpr and ApoL-1. "Only mice with ApoL-1 can kill off trypanosomes," Raper says. "But we do have evidence that Hpr can contribute."

The importance of ApoL-1 was recently shown when a farmer in India became infected byTrypanosoma evansi, which does not normally infect humans. Some feared that the parasite was adapting to humans but Pays was convinced that the farmer must have a mutation that disabled ApoL-1. He was right.

Whilst ApoL-1 protects humans against most trypanosomes, two African strains have found ways to disarm it. One isT. brucei gambiense, prevalent in western Africa. The other isT. b. rhodesiense, found in east Africa. Both cause sleeping sickness, and between them infect about 300,000 people every year.

Although rhodesiense is less common than gambiense, it is much nastier. It can kill within weeks, whereas gambiense usually takes years. The only treatment for late-stage rhodesiense is the highly toxic melarsoprol, whereas gambiense can also be cured by the less toxic (but more expensive) eflornithine.

The molecular trickery that allows gambiense to dodge ApoL-1 remains a mystery, but the story for rhodesiense is different. Back in the late 1980s, a PhD student at the Free University of Brussels (VUB) hit upon a crucial lead. "I was trying to find the molecular difference between trypanosomes that are resistant to human [blood] and those that are not," recalls Catherine De Greef, who now works for a biotech company. "I found a VSG-like molecule that is expressed only in the form of rhodesiense that infects humans."

VSG stands for "variable surface glycoprotein", the molecules that cover the surface of trypanosomes and allow them to dodge immune attack as they swim about in the bloodstream. An individual trypanosome sports just one kind of VSG but its genome harbours hundreds of gene fragments that can be mixed to produce any one of millions of different possible VSGs. So parasites with new VSGs appear faster than the immune system can learn to recognise them.

De Greef's finding, however, did not fit in with this picture of what VSGs do. "It was quite difficult to imagine how such a thing could confer resistance," Pays admits. However, he did eventually investigate the possibility - and in 1998, his team showed that adding the gene for the VSG-like molecule to strains that are normally killed by human blood enables them to survive (Cell, vol 95, p 839). De Greef was spot on.

It is now clear that rhodesiense can infect people only when it produces the mutant VSG as well as a normal VSG. The mutant VSG behaves quite differently to normal VSGs, accumulating inside lysosomes and mopping up any ApoL-1 before it makes the membrane leaky. This is what puts rhodesiense ahead in the evolutionary arms race between human and parasite.

There may, however, be a way to restore ApoL-1's killing power. When Pays's team set out to find which part of ApoL-1 actually does the damage, they began by lopping off a section they guessed was crucial. They were in for something of a surprise.

Not only was the truncated form of ApoL-1 as deadly as ever, says Pays, it even killed parasites that produced the mutant VSG that disables normal ApoL-1. It turned out that they had removed the part of ApoL-1 that the mutant VSG binds to, and thus chanced upon a new way to kill rhodesiense. "This was completely unexpected and incredibly exciting," says Pays.

The catch is delivering the ApoL-1. The assembly of the HDL particles that helps ApoL-1 enter the parasites is a carefully coordinated procedure that normally takes place in liver cells. If the truncated ApoL-1 is made outside the body, it cannot be included in HDL.

So Pays called on the expertise of Serge Muyldermans, an immunologist at the Flanders Institute for Biotechnology (VIB) in Brussels, to see if he could come up with another way to deliver the truncated ApoL- 1 to the parasite. Muyldermans has helped develop a new kind of antibody for medical treatments based on

a type originally found in camelids. Dubbed nanobodies, they are less than a tenth the size of normal antibodies.

Against all the odds, his team managed to generate a nanobody that binds to the sugar part of VSGs - the "glyco" in glycoprotein. "This would normally go undetected by the immune system," says Muyldermans. "You could try to raise a response against this hundreds of times and never get an antibody. We did it once and we had an antibody."

There was more good fortune. The target sugar seems to be a common feature of the millions of different VSGs that trypanosomes can generate. So although the parasite can change the protein portion of its VSGs to outwit the host's immune system, the sugar identified by Muyldermans's team seems to be a weak spot in its defences.

It was here that the two teams really came together. A little genetic tinkering produced a recipe for making a new protein consisting of the truncated ApoL-1 produced in Pays's lab linked to the nanobody Muyldermans created. The idea was that the ApoL-1 part would be delivered to a trypanosome when the nanobody part bound to VSGs on its surface.

It was a spectacular success. When the nanobody-ApoL-1 construct was injected into mice infected with rhodesiense, it killed off the parasite without any apparent side effects (Nature Medicine, vol 12, p 580). Initial studies suggest the construct might be effective against gambiense as well as rhodesiense.

It should work just as well in humans, too. What is not yet clear is whether it will be effective against late- stage trypanosomiasis - this depends on enough of a drug getting into the brain, and while normal nanobodies can cross the blood-brain barrier, it remains to be seen whether this is true for the construct.

For all its promise, however, there are still plenty of hurdles to clear. Antibody treatments are hardly ideal for developing countries: compared with normal drugs they are very expensive to manufacture, have to be kept refrigerated and must be injected. Using nanobodies mitigates some of these problems, since they are easier to make and are more stable than conventional antibodies, but they are still not ideal.

Worse still, the nanobody-ApoL-1 construct seems to kill off the bacteria or yeast being used to make it, causing yields to plummet. "We are working on strategies to improve the yield," Muyldermans says. "If we manage to solve the problems, I hope that someone will take this on to clinical trials." Finding that someone will be the next problem: drug companies have no interest in developing expensive treatments for diseases of the poor.

Pays remains optimistic, though, pointing out that the two teams are the first in more than half a century to come up with a new drug that is effective against rhodesiense. "Trypanosomes are amazingly versatile parasites that have a remarkable ability to outwit hosts and scientists alike," he says. "The difficulties ahead are no worse than those we've already overcome."

Henry Nicholls is a science writer based in London and author of the bookLonesome George From issue 2618 of New Scientist magazine, 22 August 2007, page 35-37

Engineering immunity

Sleeping sickness is not just a problem for people. Trypanosomes also cause a fatal disease called nagana in African livestock, which is a huge problem for farmers.

While a few local breeds of cattle are partially resistant to nagana, Etienne Pays of the Free University of Brussels (ULB) in Belgium thinks it should be possible to genetically engineer cows to make them fully resistant. He envisages adding a gene for the shortened version of the ApoL-1 protein deadly to the parasite (see main story).

Because cattle can also harbour strains of the parasite that infect people, making them resistant should benefit everyone, not just ranchers. However, creating GM cattle would be costly, and not all experts are convinced that Pays's approach would work.