Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background

Saskia Decuypere, Manu Vanaerschot, Kirstyn Brunker, Hideo Imamura, Sylke Müller, Basudha Khanal, Suman Rijal, Jean-Claude Dujardin, Graham H Coombs

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.
LanguageEnglish
Article numbere1514
Number of pages16
JournalPLOS Neglected Tropical Diseases
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 2012

Fingerprint

Leishmania
Drug Resistance
Parasites
Population
Pharmaceutical Preparations
Leishmania donovani
Nepal
Leishmaniasis
Population Genetics
Genetic Background
Sulfhydryl Compounds
Innate Immunity
Genotype
Gene Expression
Pressure
Proteins

Keywords

  • drug resistance
  • Leishmania populations
  • pathogen genotype

Cite this

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. In: PLOS Neglected Tropical Diseases. 2012 ; Vol. 6, No. 2.
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Decuypere, S, Vanaerschot, M, Brunker, K, Imamura, H, Müller, S, Khanal, B, Rijal, S, Dujardin, J-C & Coombs, GH 2012, 'Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background' PLOS Neglected Tropical Diseases, vol. 6, no. 2, e1514. https://doi.org/10.1371/journal.pntd.0001514

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.

In: PLOS Neglected Tropical Diseases, Vol. 6, No. 2, e1514, 02.2012.

Research output: Contribution to journalArticle

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AU - Vanaerschot, Manu

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