A drug for transplant patients also kills the parasites that cause African sleeping sickness by grossly distorting their shape and blocking cell division.

Trypanosoma brucei infects the tsetse fly, found only in Africa.

A drug that helps transplant patients fight tissue rejection may lead to new therapies for African sleeping sickness. The disease is fatal if left untreated, and current therapies have severe side effects.

HHMI international research scholar Miguel Navarro of the Institute of Parasitology and Biomedicine at the Spanish National Research Council in Granada, Spain, and colleagues have found that the immunosuppressant drug rapamycin kills Trypanosoma brucei, the parasite that causes African sleeping sickness. These parasites contain proteins similar to those that rapamycin inhibits in humans.

Studying how T. brucei evades the immune system, Navarro's group realized that four genes of the TOR family enable the parasite to make evasive maneuvers. The genes are called TOR because their protein products are “targets of rapamycin.” The researchers wanted to see if rapamycin could inhibit these TOR proteins. To the team's surprise, it did more than that. Rapamycin-treated parasites enlarged, sprouting multiple nuclei and other cell parts, and then they died. “They look so weird and grotesque we call them monsters,” Navarro says.

The drug doesn't cause the same cell deformities in the human immune system. In humans and all other previously studied organisms, rapamycin slows the rate of cell growth. In T. brucei, however, the drug inhibits cell division, the team discovered. Their results appeared in the September 23, 2008, issue of Proceedings of the National Academy of Sciences.

The different effects come about because humans have one TOR gene and most single-celled organisms have one or two TOR genes, but T. brucei have four. Navarro's group found that rapamycin inhibits different TOR proteins in T. brucei than in humans. The differences could be exploited to design better drugs to treat African sleeping sickness.

Because it suppresses the immune system, rapamycin could not be used directly to treat sleeping sickness in humans. But rapamycin-derived drugs that ignore immune cells are being tested as anticancer agents in clinical trials, and Navarro plans to test them
on T. brucei.

Image: Miguel Navarro and Antonio Barquilla