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      High Prevalence of Drug Resistance in Animal Trypanosomes without a History of Drug Exposure

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          Abstract

          Background

          Trypanosomosis caused by Trypanosoma congolense is a major constraint to animal health in sub-Saharan Africa. Unfortunately, the treatment of the disease is impaired by the spread of drug resistance. Resistance to diminazene aceturate (DA) in T. congolense is linked to a mutation modifying the functioning of a P2-type purine-transporter responsible for the uptake of the drug. Our objective was to verify if the mutation was linked or not to drug pressure.

          Methodology/Principal Findings

          Thirty-four T. congolense isolates sampled from tsetse or wildlife were screened for the DA-resistance linked mutation using DpnII-PCR-RFLP. The results showed 1 sensitive, 12 resistant and 21 mixed DpnII-PCR-RFLP profiles. This suggests that the mutation is present on at least one allele of each of the 33 isolates. For twelve of the isolates, a standard screening method in mice was used by (i) microscopic examination, (ii) trypanosome-specific 18S-PCR after 2 months of observation and (iii) weekly trypanosome-specific 18S-PCR for 8 weeks. The results showed that all mice remained microscopically trypanosome-positive after treatment with 5 mg/kg DA. With 10 and 20 mg/kg, 8.3% (n = 72) and 0% (n = 72) of the mice became parasitologically positive after treatment. However, in these latter groups the trypanosome-specific 18S-PCR indicated a higher degree of trypanosome-positivity, i.e., with a unique test, 51.4% (n = 72) and 38.9% (n = 72) and with the weekly tests 79.2% (n = 24) and 66.7% (n = 24) for 10 and 20 mg/kg respectively.

          Conclusion/Significance

          The widespread presence of the DA-resistance linked mutation in T. congolense isolated from wildlife suggests that this mutation is favourable to parasite survival and/or its dissemination in the host population independent from the presence of drug. After treatment with DA, those T. congolense isolates cause persisting low parasitaemias even after complete elimination of the drug and with little impact on the host's health.

          Author Summary

          Trypanosomosis is responsible for the death of 3 million heads of cattle yearly, with 50 million animals at risk in sub-Saharan Africa. DA, a commonly used drug against the disease, was marketed decades ago. Drug resistance is reported in 21 African countries. A common argument about the origin of drug resistance is the selection by the drug of rare individuals that are naturally resistant and the propagation of those individuals in the population because of the competitive advantage they have when exposed to drug. When the drug pressure decreases, the wild-type individuals regain their supremacy. The principal objective of this study was thus to estimate the prevalence of trypanosomes resistant to DA in a population that was never exposed to the drug. Our results showing a high prevalence of drug resistance in environments free of any drug pressure is thought provoking and suggests that ceasing the use of DA will not allow for a return to a DA-sensitive population of trypanosomes. Drug resistance in animal trypanosomes thus present a pattern different from what is observed with Plasmodium sp. (causative agent of malaria) where a complete stoppage in the use of the chloroquine allows for a return to drug sensitivity.

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          Most cited references 52

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          A nucleoside transporter from Trypanosoma brucei involved in drug resistance.

          Drug resistance of pathogens is an increasing problem whose underlying mechanisms are not fully understood. Cellular uptake of the major drugs against Trypanosoma brucei spp., the causative agents of sleeping sickness, is thought to occur through an unusual, so far unidentified adenosine transporter. Saccharomyces cerevisiae was used in a functional screen to clone a gene (TbAT1) from Trypanosoma brucei brucei that encodes a nucleoside transporter. When expressed in yeast, TbAT1 enabled adenosine uptake and conferred susceptibility to melaminophenyl arsenicals. Drug-resistant trypanosomes harbor a defective TbAT1 variant. The molecular identification of the entry route of trypanocides opens the way to approaches for diagnosis and treatment of drug-resistant sleeping sickness.
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            The origins of antimalarial drug resistance.

             Ian Hastings (2004)
            Resistance of Plasmodium falciparum to the antimalarial drug sulfadoxine-pyrimethamine is a result of extremely rare mutations that have spread over large geographical areas. This pattern was completely unexpected because mutations encoding resistance occur commonly in laboratory conditions, leading to the expectation that resistance would originate locally on numerous occasions. This can be reconciled with basic P. falciparum biology and epidemiology, and it is concluded that this pattern of extremely rare mutations and subsequent spread should be regarded as the most likely pattern of resistance to future antimalarials. Consequently, strategies to slow the spread of resistance need to be designed on regional, rather than national, considerations.
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              Molecular tools for the rapid detection of drug resistance in animal trypanosomes.

              There are currently 17 African countries in which animal trypanocidal drug resistance has been reported. Large-scale surveys were carried out in only ten of them. The lack of baseline information is mainly due to the fact that the methods currently available for the detection of drug resistance are laborious, expensive and time consuming. In this review the mechanisms involved in resistance to isometamidium and diminazene will be discussed, together with some new molecular detection tools that have been developed recently enabling faster diagnosis of drug resistance than conventional laboratory or field tests.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                December 2011
                20 December 2011
                : 5
                : 12
                Affiliations
                [1 ]Institute of Tropical Medicine Antwerp, Antwerp, Belgium
                [2 ]Department of Paraclinical Studies, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia
                [3 ]Department of Veterinary Tropical Diseases, University of Pretoria, Onderstepoort, South Africa
                Swiss Tropical and Public Health Institute, Switzerland
                Author notes

                Conceived and designed the experiments: SC PVdB JVDA VD. Performed the experiments: SC VD. Analyzed the data: TM BN VD. Contributed reagents/materials/analysis tools: PVdB JVDA. Wrote the paper: SC TM BN JVDA VD.

                Article
                PNTD-D-11-00909
                10.1371/journal.pntd.0001454
                3243716
                22206039
                Chitanga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 5
                Categories
                Research Article
                Biology
                Microbiology
                Protozoology
                Veterinary Science
                Veterinary Diseases
                Veterinary Parasitology

                Infectious disease & Microbiology

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