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Author Notes:

E-mail: marcuslacerda.br@gmail.com; kuppal2@emory.edu

for a full list of author contributions, see full article

We are grateful to the patients and clinical staff at the FMT-HVD and all members of the MaHPIC Consortium, particularly Esmeralda VS Meyer for supportive managerial aspects of this collaboration.

The authors have declared that no competing interests exist.

Subject:

Research Funding:

This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases; National Institutes of Health, Department of Health and Human Services [Contract No. HHSN272201200031C] to MRG, and the National Center for Research Resources [ORIP/OD P51OD011132]. JLS and FV were supported by the Fogarty International Center Global Health Fellowship [R25TW009337]. MVGL and WMM were supported by CAPES, CNPq and FAPEAM.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • ANTIMALARIAL-DRUG RESISTANCE
  • HIGH-RESOLUTION METABOLOMICS
  • BRAZILIAN AMAZON
  • MASS-SPECTROMETRY
  • FALCIPARUM MALARIA
  • DIGESTIVE VACUOLE
  • HEME-BINDING
  • BOX REVEALS
  • CRT-O
  • POLYMERIZATION

Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

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Journal Title:

PLoS ONE

Volume:

Volume 12, Number 8

Publisher:

, Pages e0182819-e0182819

Type of Work:

Article | Final Publisher PDF

Abstract:

BACKGROUND: Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. METHODS: An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. RESULTS: Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. CONCLUSIONS: The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus CQ-S patients prior to antimalarial treatment. Metabolomics phenotyping of P. vivax samples from patients with well-defined clinical CQ-resistance is promising for the development of new tools to understand the biological process and to identify potential biomarkers of PvCR.

Copyright information:

© 2017 Uppal et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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