The team, led by researchers from the London School of Hygiene and Tropical Medicine (LSHTM), hopes the results will eventually lead to better treatments.
Human African trypanosomiasis, also known as sleeping sickness, is a serious parasitic infection that attacks the central nervous system. The single-celled parasite responsible, Trypanosoma brucei, is transmitted by the tsetse fly and causes around 30 000 deaths per year in sub-Saharan Africa. Current drug regimes, which include the arsenic-based compound melarsoprol, are becoming increasingly ineffective as T. brucei develops resistance to them. These drugs also have a range of unpleasant side-effects.
To combat the rise of drug-resistant parasites and develop less toxic treatments, scientists at the LSHTM led a collaboration that screened the genome of T. brucei to find genes related to the actions of various medications used to treat the disease.
The researchers used a new technique called RNA interference target sequencing, developed at the LSHTM. This relied on high-throughput DNA sequencing conducted at the Wellcome Trust Sanger Institute, near Cambridge.
The approach involves the disruption of gene expression in T. brucei. The function of a single, specific gene was knocked out in each parasite treated with existing drugs. Applying this method in parallel in many thousands of parasites allowed coverage of the T. brucei genome, gene by gene, and meant that researchers could infer which genes interacted with the different drugs.
After screening almost 7500 genes, the new study identifies 50 that – along with their corresponding protein products – relate to how the drugs work. The biological properties of the 50 proteins were also examined to document exactly how each of these interact with the drugs.
“This new understanding of how these medications kill parasites, or fail to kill parasites, could lead to the development of tests that guide the intervention strategy, as well as more active and safer intervention options,” explains lead researcher Dr David Horn, from the LSHTM. “What is important now is to begin the process of translating the new findings into clinical advances such as new diagnostics and therapies.”
Image: An SEM of a Trypanosoma brucei brucei parasite, showing a replicating bloodstream trypomastigote. Credit: Gull Lab, Sir William Dunn School of Pathology, Wellcome Images.
Alsford S et al. High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature 2012 (in press).