Trypanosoma brucei is the causative agent of human African trypanosomiasis, known as sleeping sickness. The World Health Organisation puts the number of cases in sub-Saharan Africa at 300,000 to 500,000. From being responsible for a few thousand deaths in 1960, this disease went on to account for 50,000 deaths in 2002. The parasite is transmitted to the mammalian host by a fly of the genus Glossina, known as the tsetse fly. The disease is characterised by intermittent fevers which coincide with peaks of parasitaemia. When the parasites cross the blood-brain barrier and invade the cerebrospinal fluid, the neurological stage of the disease begins, with the characteristic symptomatology that includes headaches, confusion, alterations to the sleep cycle and, finally, brain coma.
Without medical treatment, this disease is lethal, and development of an effective vaccine is hindered by antigenic variation on the surface of the parasite. Currently, the drugs used have the drawback of not being effective in the different stages of the disease and/or possessing a very high degree of toxicity. Our research project focuses on the so-called target of rapamycin proteins (TbTORs), kinases that regulate cell growth in this parasite. Although these proteins regulate growth overall, each of them controls a specific aspect of such growth. Whereas TbTOR1 positively regulates processes aimed at the accumulation of cell mass, TbTOR2 ensures that such cell-growth and -division processes take place appropriately.
Rapamycin is a macrolide-type drug capable of bonding with very high affinity to the protein FKBP12, and this complex bonds to TOR both in yeast and in humans, which inhibits the kinase activity of TOR, leading to a halt in the cell cycle's G1/S phase and a decline in protein synthesis, namely, inhibition of cellular proliferation and growth. This makes rapamycin a very effective antiproliferative drug, used as an antifungicide, antitumoral and immunosuppressor, and TORs, a good therapeutic target owing to the fact that they are central regulators of signalling cascade, the function of which is essential for cell survival. Rapamycin selectively inhibits TORC1, while TORC2 is resistant to this drug. We recently identified that -unlike other eukaryotes- in T. brucei, rapamycin inhibits cell proliferation through exclusive inhibition of the TORC2 signal. These and other differences observed both in TOR proteins and in rapamycin action between humans and trypanosomes, will be the basis for the search for rapamycin derivatives with a selective trypanocidal action.
Head Researcher Miguel Navarro
López-Neyra Institute of Parasitology and Biomedicine
Scientific Research Board
CSIC (Consejo Superior de Investigaciones Científicas)
Avda. del Conocimiento s/n
18100 GRANADA