Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/31841
Title: Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria
Authors: Uppal, Karan
Salinas, Jorge L.
Monteiro, Wuelton M.
Val, Fernando
Cordy, Regina J.
Liu, Ken
Melo, Gisely C.
Siqueira, Andre M.
Magalhães, Belisa
Galinski, Mary R.
Lacerda, Marcus V. G.
Jones, Dean P.
Affilliation: Emory University. Department of Medicine. Clinical Biomarkers Laboratory. Division of Pulmonary Medicine. Atlanta, GA, USA / Malaria Host–Pathogen Interaction Center. Atlanta, GA, USA.
Malaria Host–Pathogen Interaction Center. Atlanta, GA, USA / Emory University. International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center. Atlanta, GA, USA / Emory University. Emory Vaccine Center. Atlanta, GA, USA /Emory University. Yerkes National Primate Research Center. Atlanta, GA, USA / Emory University. Rollins School of Public Health. Atlanta, GA, USA.
Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.
Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.
Malaria Host–Pathogen Interaction Center. Atlanta, GA, USA / Emory University. International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center. Atlanta, GA, USA / Emory University. Emory Vaccine Center. Atlanta, GA, USA /Emory University. Yerkes National Primate Research Center. Atlanta, GA, USA.
Emory University. Department of Medicine. Clinical Biomarkers Laboratory. Division of Pulmonary Medicine. Atlanta, GA, USA
Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Universidade do Estado do Amazonas. Manaus, AM, Brasil.
Malaria Host–Pathogen Interaction Center. Atlanta, GA, USA / Emory University. International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center. Atlanta, GA, USA / Emory University. Emory Vaccine Center. Atlanta, GA, USA /Emory University. Yerkes National Primate Research Center. Atlanta, GA, USA / Emory University. Rollins School of Public Health. Atlanta, GA, USA.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.
Emory University. Department of Medicine. Clinical Biomarkers Laboratory. Division of Pulmonary Medicine. Atlanta, GA, USA / Malaria Host–Pathogen Interaction Center. Atlanta, GA, USA.
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 nd 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.
Keywords: Plasmodium vivax
Malaria
Chloroquine
Issue Date: 2017
Publisher: Public Library of Science
Citation: UPPAI, Karan et al. Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria. Plos One, p. 1-20, 16 Aug. 2017.
DOI: 10.1371/journal.pone.0182819
ISSN: 1932-6203
Copyright: open access
Appears in Collections:INI - Artigos de Periódicos

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