Metabolomics to unveil and understand phenotypic diversity between pathogen populations

Ruben t'Kindt, Richard A Scheltema, Andris Jankevics, Kirstyn Brunker, Suman Rijal, Jean-Claude Dujardin, Rainer Breitling, David G Watson, Graham H Coombs, Saskia Decuypere

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Leishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to antimonial treatment due to differing intrinsic drug sensitivity of the parasites. Here, we present a proof-of-principle study in which we applied a metabolomics pipeline specifically developed for L. donovani to characterize the global metabolic differences between antimonial-sensitive and antimonial-resistant L. donovani isolates. Clones of drug-sensitive and drug-resistant parasite isolates from clinical samples were cultured in vitro and harvested for metabolomics analysis. The relative abundance of 340 metabolites was determined by ZIC-HILIC chromatography coupled to LTQ-Orbitrap mass spectrometry. Our measurements cover approximately 20% of the predicted core metabolome of Leishmania and additionally detected a large number of lipids. Drug-sensitive and drug-resistant parasites showed distinct metabolic profiles, and unsupervised clustering and principal component analysis clearly distinguished the two phenotypes. For 100 metabolites, the detected intensity differed more than three-fold between the 2 phenotypes. Many of these were in specific areas of lipid metabolism, suggesting that the membrane composition of the drug-resistant parasites is extensively modified. Untargeted metabolomics has been applied on clinical Leishmania isolates to uncover major metabolic differences between drug-sensitive and drug-resistant isolates. The identified major differences provide novel insights into the mechanisms involved in resistance to antimonial drugs, and facilitate investigations using targeted approaches to unravel the key changes mediating drug resistance.
LanguageEnglish
Article numbere904
Number of pages12
JournalPLOS Neglected Tropical Diseases
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2010

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Metabolomics
Parasites
Pharmaceutical Preparations
Population
Leishmania donovani
Leishmania
Metabolome
Phenotype
Nepal
Leishmaniasis
Visceral Leishmaniasis
Principal Component Analysis
Lipid Metabolism
Drug Resistance
Cluster Analysis
Chromatography
Mass Spectrometry
Clone Cells
Lipids
Membranes

Keywords

  • Leishmania donovani promastigotes
  • LC-MS data
  • pentamidine resistant Leishmania
  • in-vitro sisceptibility
  • visceral Leishmaniasis
  • mass-spectrometry
  • amphotericin-b
  • lipid-metabolism
  • genes

Cite this

t'Kindt, R., Scheltema, R. A., Jankevics, A., Brunker, K., Rijal, S., Dujardin, J-C., ... Decuypere, S. (2010). Metabolomics to unveil and understand phenotypic diversity between pathogen populations. PLOS Neglected Tropical Diseases, 4(11), [e904]. https://doi.org/10.1371/journal.pntd.0000904
t'Kindt, Ruben ; Scheltema, Richard A ; Jankevics, Andris ; Brunker, Kirstyn ; Rijal, Suman ; Dujardin, Jean-Claude ; Breitling, Rainer ; Watson, David G ; Coombs, Graham H ; Decuypere, Saskia. / Metabolomics to unveil and understand phenotypic diversity between pathogen populations. In: PLOS Neglected Tropical Diseases. 2010 ; Vol. 4, No. 11.
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t'Kindt, R, Scheltema, RA, Jankevics, A, Brunker, K, Rijal, S, Dujardin, J-C, Breitling, R, Watson, DG, Coombs, GH & Decuypere, S 2010, 'Metabolomics to unveil and understand phenotypic diversity between pathogen populations' PLOS Neglected Tropical Diseases, vol. 4, no. 11, e904. https://doi.org/10.1371/journal.pntd.0000904

Metabolomics to unveil and understand phenotypic diversity between pathogen populations. / t'Kindt, Ruben; Scheltema, Richard A; Jankevics, Andris; Brunker, Kirstyn; Rijal, Suman; Dujardin, Jean-Claude; Breitling, Rainer; Watson, David G; Coombs, Graham H; Decuypere, Saskia.

In: PLOS Neglected Tropical Diseases, Vol. 4, No. 11, e904, 11.2010.

Research output: Contribution to journalArticle

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AU - t'Kindt, Ruben

AU - Scheltema, Richard A

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AU - Dujardin, Jean-Claude

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