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:	Saskia Decuypere, Manu Vanaerschot, Kirstyn Brunker, Hideo Imamura, Sylke Müller, Basudha Khanal, Suman Rijal, Jean-Claude Dujardin, Graham H Coombs
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/3cc11c779a5c45b59e37c9791843ce84
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spelling	oai:doaj.org-article:3cc11c779a5c45b59e37c9791843ce842021-11-18T09:14:25ZMolecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.1935-27271935-273510.1371/journal.pntd.0001514https://doaj.org/article/3cc11c779a5c45b59e37c9791843ce842012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22389733/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735The 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.Saskia DecuypereManu VanaerschotKirstyn BrunkerHideo ImamuraSylke MüllerBasudha KhanalSuman RijalJean-Claude DujardinGraham H CoombsPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 6, Iss 2, p e1514 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Saskia Decuypere Manu Vanaerschot Kirstyn Brunker Hideo Imamura Sylke Müller Basudha Khanal Suman Rijal Jean-Claude Dujardin Graham H Coombs Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.
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.
format	article
author	Saskia Decuypere Manu Vanaerschot Kirstyn Brunker Hideo Imamura Sylke Müller Basudha Khanal Suman Rijal Jean-Claude Dujardin Graham H Coombs
author_facet	Saskia Decuypere Manu Vanaerschot Kirstyn Brunker Hideo Imamura Sylke Müller Basudha Khanal Suman Rijal Jean-Claude Dujardin Graham H Coombs
author_sort	Saskia Decuypere
title	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_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_sort	molecular mechanisms of drug resistance in natural leishmania populations vary with genetic background.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3cc11c779a5c45b59e37c9791843ce84
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Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.

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