Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum

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10 Citations (Scopus)

Abstract

Background. The emergence of artemisinin resistance in the malaria parasite Plasmodium falciparum poses a major threat to the control and elimination of malaria. Certain point mutations in the propeller domain of PfKelch13 are associated with resistance, but PfKelch13 mutations do not always result in clinical resistance. The underlying mechanisms associated with artemisinin resistance are poorly understood, and the impact of PfKelch13 mutations on cellular biochemistry is not defined. 

Methods. This study aimed to identify global biochemical differences between PfKelch13-mutant artemisinin-resistant and -sensitive strains of P. falciparum by combining liquid chromatography-mass spectrometry (LC-MS)-based proteomics, peptidomics, and metabolomics. 

Results. Proteomics analysis found both PfKelch13 mutations examined to be specifically associated with decreased abundance of PfKelch13 protein. Metabolomics analysis demonstrated accumulation of glutathione and its precursor, gamma-glutamylcysteine, and significant depletion of 1 other putative metabolite in resistant strains. Peptidomics analysis revealed lower abundance of several endogenous peptides derived from hemoglobin (HBα and HBβ) in the artemisinin-resistant strains. 

Conclusion. PfKelch13 mutations associated with artemisinin resistance lead to decreased abundance of PfKelch13 protein, decreased hemoglobin digestion, and enhanced glutathione production.

Original languageEnglish
Pages (from-to)1435-1444
Number of pages10
JournalJournal of Infectious Diseases
Volume215
Issue number9
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • artemisinin resistance
  • malaria
  • metabolomics
  • peptidomics
  • PfKelch13
  • Plasmodium falciparum
  • proteomics

Cite this

@article{1748c24feb94404789b5861b0addcb72,
title = "Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum",
abstract = "Background. The emergence of artemisinin resistance in the malaria parasite Plasmodium falciparum poses a major threat to the control and elimination of malaria. Certain point mutations in the propeller domain of PfKelch13 are associated with resistance, but PfKelch13 mutations do not always result in clinical resistance. The underlying mechanisms associated with artemisinin resistance are poorly understood, and the impact of PfKelch13 mutations on cellular biochemistry is not defined. Methods. This study aimed to identify global biochemical differences between PfKelch13-mutant artemisinin-resistant and -sensitive strains of P. falciparum by combining liquid chromatography-mass spectrometry (LC-MS)-based proteomics, peptidomics, and metabolomics. Results. Proteomics analysis found both PfKelch13 mutations examined to be specifically associated with decreased abundance of PfKelch13 protein. Metabolomics analysis demonstrated accumulation of glutathione and its precursor, gamma-glutamylcysteine, and significant depletion of 1 other putative metabolite in resistant strains. Peptidomics analysis revealed lower abundance of several endogenous peptides derived from hemoglobin (HBα and HBβ) in the artemisinin-resistant strains. Conclusion. PfKelch13 mutations associated with artemisinin resistance lead to decreased abundance of PfKelch13 protein, decreased hemoglobin digestion, and enhanced glutathione production.",
keywords = "artemisinin resistance, malaria, metabolomics, peptidomics, PfKelch13, Plasmodium falciparum, proteomics",
author = "Ghizal Siddiqui and Anubhav Srivastava and Russell, {Adrian S} and Creek, {Darren J}",
year = "2017",
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Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum. / Siddiqui, Ghizal; Srivastava, Anubhav; Russell, Adrian S; Creek, Darren J.

In: Journal of Infectious Diseases, Vol. 215, No. 9, 01.05.2017, p. 1435-1444.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum

AU - Siddiqui, Ghizal

AU - Srivastava, Anubhav

AU - Russell, Adrian S

AU - Creek, Darren J

PY - 2017/5/1

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N2 - Background. The emergence of artemisinin resistance in the malaria parasite Plasmodium falciparum poses a major threat to the control and elimination of malaria. Certain point mutations in the propeller domain of PfKelch13 are associated with resistance, but PfKelch13 mutations do not always result in clinical resistance. The underlying mechanisms associated with artemisinin resistance are poorly understood, and the impact of PfKelch13 mutations on cellular biochemistry is not defined. Methods. This study aimed to identify global biochemical differences between PfKelch13-mutant artemisinin-resistant and -sensitive strains of P. falciparum by combining liquid chromatography-mass spectrometry (LC-MS)-based proteomics, peptidomics, and metabolomics. Results. Proteomics analysis found both PfKelch13 mutations examined to be specifically associated with decreased abundance of PfKelch13 protein. Metabolomics analysis demonstrated accumulation of glutathione and its precursor, gamma-glutamylcysteine, and significant depletion of 1 other putative metabolite in resistant strains. Peptidomics analysis revealed lower abundance of several endogenous peptides derived from hemoglobin (HBα and HBβ) in the artemisinin-resistant strains. Conclusion. PfKelch13 mutations associated with artemisinin resistance lead to decreased abundance of PfKelch13 protein, decreased hemoglobin digestion, and enhanced glutathione production.

AB - Background. The emergence of artemisinin resistance in the malaria parasite Plasmodium falciparum poses a major threat to the control and elimination of malaria. Certain point mutations in the propeller domain of PfKelch13 are associated with resistance, but PfKelch13 mutations do not always result in clinical resistance. The underlying mechanisms associated with artemisinin resistance are poorly understood, and the impact of PfKelch13 mutations on cellular biochemistry is not defined. Methods. This study aimed to identify global biochemical differences between PfKelch13-mutant artemisinin-resistant and -sensitive strains of P. falciparum by combining liquid chromatography-mass spectrometry (LC-MS)-based proteomics, peptidomics, and metabolomics. Results. Proteomics analysis found both PfKelch13 mutations examined to be specifically associated with decreased abundance of PfKelch13 protein. Metabolomics analysis demonstrated accumulation of glutathione and its precursor, gamma-glutamylcysteine, and significant depletion of 1 other putative metabolite in resistant strains. Peptidomics analysis revealed lower abundance of several endogenous peptides derived from hemoglobin (HBα and HBβ) in the artemisinin-resistant strains. Conclusion. PfKelch13 mutations associated with artemisinin resistance lead to decreased abundance of PfKelch13 protein, decreased hemoglobin digestion, and enhanced glutathione production.

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