Sleeping sickness: Good night, arsenic!

3. June 2011

Trypanosomes – single-celled spiral-shaped cells – cause the African illness Sleeping Sickness. Since it mainly affects developing countries, over the years the interest in researching it has been low. There are now several approaches to treating it that could lead to new therapies.

On the run from violence and civil war, refugees are moving ever more into the once sparsely populated savannah – home to billions of hungry tsetse flies. Currently, according to the World Health Organisation (WHO), three million people are infected and the majority of pharmaceutical companies show a lack of interest in conducting research into new treatment strategies – the representatives of the World Health Authority talk not without justifaction of “neglected tropical diseases.” Recently, the Federal Ministry of Education and Research of Germany has therefore made 20 million euros more openly available in order to advance diagnosis, therapy and prevention.

Flying Syringes

It is tsetse flies in particular which transmit the protozoa Trypanosoma brucei. When feeding, they secrete a substance in order to prevent blood clotting. This process permits trypanosomes to enter the human body. A few weeks after the infection there is fever, headache and limb pain, as well as swelling of the lymph nodes. At times patients also complain of itching or skin rashes. After several months, the responsible agents move into the nervous system and neurological symptoms are inevitable: confusion, convulsions, a penultimate comatose period, and finally death.

“There are some drugs that act against sleeping sickness, but they are all extremely problematic,” says Professor Dr. Michael Duszenko from the University of Tübingen. Suramin or pentamidine for instance help only in the initial stage – these drugs can’t overcome the blood-brain barrier. Melarsoprol does get involved in the later stages, but it contains arsenic, so that “many people die from the treatment, and not from the disease.” Eflornithine on the other hand is considered expensive, difficult to obtain and not always effective.

Stinging forbidden

Alongside closed, light-colored clothes in offering known protection against the sucking pests is, above all else, chemical deterrent. There is still a great need for education: recent survey of backpackers showed that only 54 percent used such measures – even though their treks were planned in high risk areas. One Swiss group delved into the matter of gender differences in relation to the disease. Its conclusion: Men are affected more frequently than women from infectious diseases such as Trypanosomiasis.
Higher risk-taking in combination with inadequate safeguards could offer one explanation.

A good disguise is half the battle

Why trypanosomes can survive in the blood after a bite and not be attacked by antibodies for a long time was unclear. Now this process has been largely determined. “People acquire no immunity against the sleeping sickness because the immune reaction doesn’t take hold and initiates no immune memory,” emphasises Michael Duszenko. Trypanosomes have on their surface a wealth of theoretically very detectable glycoproteins. The protozoa however constantly changes them: Several research groups found in the genome of the blood parasites more than 1000 different genes that it can selectively either turn off or on. This guarantees Trypanosoma that a certain proportion of the population survives in the host and can transform again in the multiplication: In the blood, the number of trypanosomes at first decreases and then increases again. Duszenko: “The cycles (of protozoan replication) come into being due to the fact that the human immune system makes antibodies against the surface protein, so that the parasites largely perish.” However, individual representatives survive by creating new antigens, with which the human immune system can’t cope. If left untreated, the fluctuations repeat right up to the point of death of patients.
Professor Dr. Markus Engstler from the Max Planck Institute for Dynamics and Self-Organization in Göttingen together with colleagues from the TU Darmstadt found another approach that offer an explanation: The blood parasites swim steadily forward, creating a strong current by cellular standards. If antibodies of the immune system bind, they happen to head toward the rear end of these protozoa. There they can gather up quickly and thus be inactivated. When researchers made genetic changes to Trypanosoma which cause them to roll in reverse, there was no escape for them – antibodies, once bound, could accomplish their action of destruction.

Mosquito 2.0

In order to reduce the overall population of tsetse flies, the Austrian evolutionary biologist Professor Dr. Helmut Kratochvil is pursuing a specific strategy: using radiation he produces sterile males. Using a specially designed acoustic testing procedure for differentiating and identifying them, Kratochvil ascertains the call activity – only the most agile individuals are to eventually head forth on the long trip to various regions of Africa. In the absence of the sucking pests’ offspring, the trypanosome infestation is also reduced. In order to thwart one million females, however, the professor needs about nine million sterile males: an immense undertaking.

Attentive research

Nevertheless, new drugs are needed. Researchers at the University of Dundee, UK, discovered a potential Achilles heel in Trypanosoma brucei. They inhibited the parasite enzyme N-myristoyltransferase with a special pyrazolsulfonamide. In mice, the treatment worked reliably, and without major side effects. The authors expect in the event of a possible approval with an inexpensive pharmacological medium that it would be taken orally – two big advantages for future use. Another metabolic step is being scrutinised by scientists from Italy, Germany and Belgium. They developed, by computer, chemical structures which cut off both dihydrofolate reductase and pteridinreduktase, two important enzymes in trypanosomes. After this theoretical step then followed practice: In the laboratory, 18 possible molecular candidates were tested. An old well-known example was to become the favorite: Riluzole, a benzothiazole, which is already used for the treatment of amyotrophic lateral sclerosis.

In contrast, research work at the Ruhr-University Bochum on the disruption of cellular energy supply is highly regarded. One potential drug candidate in this case is supposed to only block glycosome, that is the special cellular mini power plants in these blood parasites.

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