New insights into drug targets for sleeping sickness

An enzyme which allows trypanosome parasites to evade human defences is a promising target for new drugs, according to a study in PLOS Pathogens.

Seventy million people in sub-Saharan Africa are at risk of contracting sleeping sickness - a potentially fatal disease which attacks the central nervous system causing changes in personality, seizures and difficulty in walking and talking. The disease is caused by Trypanosome parasites transmitted by tsetse flies, however, different subspecies infect different hosts - Trypanosoma brucei brucei infects cattle but is non-infectious to humans, whereas T. b. gambiense and T. b. rhodesiense display specific adaptations that allow them to cause human disease.

By searching for genes that make T. b. brucei sensitive to the innate defences of the human immune system, a team from the London School of Hygiene & Tropical Medicine have now identified an enzyme and a previously unknown gene which interact with human defences.

The team screened all 7,500 genes in the T. b. brucei parasite by systematically inactivating each gene and looking for parasites which could survive exposure to human blood serum. In their search, they identified four genes that make T. b. brucei sensitive to human defences. This included the discovery of a previously unknown gene, and they were also able to reveal more detail on the mechanism behind the role of another gene, ICP.

When ICP was inactivated, an enzyme called CATL became fully active and counteracted the components of human serum responsible for killing trypanosomes. As this appears to be an important defence mechanism for the parasite, the authors suggest this makes CATL a particularly attractive drug target for human-infectious trypanosomes.

Lead author Dr Sam Alsford, Senior Lecturer in Molecular Parasitology at the London School of Hygiene & Tropical Medicine, said: "New drugs for sleeping sickness are urgently needed because the existing ones have serious side effects.  These new results are helping us to reveal more about what makes some trypanosomes resistant to human defences, while others are sensitive. CATL is an important drug target, and our work suggests that inhibiting this enzyme could help support the human defence system in fighting off the disease."

The researchers plan to carry out further work on the new gene they discovered, which they say is likely to be involved in the parasite's uptake of human defence factors from the blood, and could play an important role in its interaction with human defences.

The research was funded by the MRC and Wellcome Trust

Alsford S, Currier RB, Guerra-Assunção JA, Clark TG, Horn D (2014). Cathepsin-L Can Resist Lysis by Human Serum in Trypanosoma brucei brucei. PLoS Pathog 10(5): e1004130. DOI: 10.1371/journal.ppat.1004130

For further information on the research, visit Dr Sam Alsford's blog

Video: Trypanosoma brucei brucei trypomastigote stage. Cattle infectious subspecies in axenic asynchronous culture. Recorded in real time. Credit: Science Photo Library / London School of Hygiene & Tropical Medicine

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