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Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom bee...

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Autores principales: Decuypere, Saskia, Vanaerschot, Manu, Brunker, Kirstyn, Imamura, Hideo, Müller, Sylke, Khanal, Basudha, Rijal, Suman, Dujardin, Jean-Claude, Coombs, Graham H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289598/
https://www.ncbi.nlm.nih.gov/pubmed/22389733
http://dx.doi.org/10.1371/journal.pntd.0001514
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author Decuypere, Saskia
Vanaerschot, Manu
Brunker, Kirstyn
Imamura, Hideo
Müller, Sylke
Khanal, Basudha
Rijal, Suman
Dujardin, Jean-Claude
Coombs, Graham H.
author_facet Decuypere, Saskia
Vanaerschot, Manu
Brunker, Kirstyn
Imamura, Hideo
Müller, Sylke
Khanal, Basudha
Rijal, Suman
Dujardin, Jean-Claude
Coombs, Graham H.
author_sort Decuypere, Saskia
collection PubMed
description The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability.
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spelling pubmed-32895982012-03-02 Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background Decuypere, Saskia Vanaerschot, Manu Brunker, Kirstyn Imamura, Hideo Müller, Sylke Khanal, Basudha Rijal, Suman Dujardin, Jean-Claude Coombs, Graham H. PLoS Negl Trop Dis Research Article The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability. Public Library of Science 2012-02-28 /pmc/articles/PMC3289598/ /pubmed/22389733 http://dx.doi.org/10.1371/journal.pntd.0001514 Text en Decuypere et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Decuypere, Saskia
Vanaerschot, Manu
Brunker, Kirstyn
Imamura, Hideo
Müller, Sylke
Khanal, Basudha
Rijal, Suman
Dujardin, Jean-Claude
Coombs, Graham H.
Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title_full Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title_fullStr Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title_full_unstemmed Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title_short Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background
title_sort molecular mechanisms of drug resistance in natural leishmania populations vary with genetic background
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289598/
https://www.ncbi.nlm.nih.gov/pubmed/22389733
http://dx.doi.org/10.1371/journal.pntd.0001514
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