A scientist from the University of Glasgow, in partnership with others from the London School of Tropical Medicine, has uncovered the genetic basis for drug resistance in sleeping sickness.

Dr Harry De Koning, Reader of Biochemical Parasitology at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, together with Dr David Horn and his colleagues at the London School of Hygiene and Tropical Medicine (LSHTM), have identified a genetic marker which will show whether a patient is resistant to drug treatment for African sleeping sickness.

African sleeping sickness, caused by infection with unicellular parasite Trypanosoma brucei, is endemic in many Sub-Saharan countries and almost invariably fatal.

Disease control relies almost entirely on chemotherapy as control of the tsetse fly vector is impracticable in the vast areas affected, and there is no vaccine.

Unfortunately, there are only a few, highly unsatisfactory drugs available to treat this infection. If the disease is diagnosed early, with the parasite proliferating in the peripheral bloodstream, the disease can usually be treated with injections of pentamidine but at the later stage, when the parasites have also penetrated the central nervous system, the routine treatment is with the arsenic-based drug melarsoprol, which is dangerously toxic and causes the death of an estimated 5% of the patients treated with it. Both drugs were introduced in the 1930s and their prolonged use has led to resistance in the parasites.

It has been known for decades that resistance to one of these drugs is usually associated with resistance to the other one as well, known as melarsoprol-pentamidine cross-resistance (MPXR), but for a long time the reason for this remained unknown.

Dr Harry de Koning discovered a few years ago that certain transport proteins on the surface of the trypanosome were involved in allowing both drugs entry into the parasite cell; loss of these transporters caused the MPXR phenotype. This discovery led to an effort to identify the genes controlling these transporters, funded by the Medical Research Council.

In a separate research programme, Dr David Horn and colleagues at LSHTM recently identified a cluster of channels for water and small metabolites (Aquaglyceroporins) in the Trypanosoma genome as a genetic determinant for MPXR (Nature 482:232-236). This resulted in a highly productive collaboration between the LSHTM and Glasgow teams. The findings, now published in the journal Proceedings of the National Academy of Sciences of the U.S.A., revealed that one of the water/metabolite channels, Trypanosoma brucei Aquaglyceroporin 2, is indeed the genetic determinant of MPXR as deletion of this one gene (but not of other channels) caused significant resistance to both drugs. In addition, the gene was found to be disrupted in multi-drug resistant trypanosomes.

Identification of a genetic marker for multi-drug resistance will finally enable investigations into the scale of the MPXR problem in endemic countries and will hopefully prove to be sufficiently robust to underpin treatment decisions for individual patients who will then be spared dangerous treatment that would not cure them.

For more information, contact Cara MacDowall on 0141 330 3683 or email cara.macdowall@glasgow.ac.uk

First published: 21 June 2012

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