Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics

Stije J. Leopold, Aniruddha Ghose, Erik L. Allman, Hugh W.F. Kingston, Amir Hossain, Asok Kumar Dutta, Katherine Plewes, Kesinee Chotivanich, Nicholas P.J. Day, Joel Tarning, Markus Winterberg, Nicholas J. White, Manuel Llinas, Arjen M. Dondorp

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background. Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. Methods. A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. Results. We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. Conclusions. These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria.

Original languageEnglish (US)
Pages (from-to)1766-1776
Number of pages11
JournalJournal of Infectious Diseases
Volume219
Issue number11
DOIs
StatePublished - Jun 1 2019

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Metabolomics
Falciparum Malaria
Acidosis
Acids
Malaria
Parasites
Plasmodium falciparum
Citrulline
Bangladesh
Life Cycle Stages
Liquid Chromatography
Observational Studies
Mass Spectrometry
Prospective Studies
Mortality

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Leopold, S. J., Ghose, A., Allman, E. L., Kingston, H. W. F., Hossain, A., Dutta, A. K., ... Dondorp, A. M. (2019). Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics. Journal of Infectious Diseases, 219(11), 1766-1776. https://doi.org/10.1093/infdis/jiy727
Leopold, Stije J. ; Ghose, Aniruddha ; Allman, Erik L. ; Kingston, Hugh W.F. ; Hossain, Amir ; Dutta, Asok Kumar ; Plewes, Katherine ; Chotivanich, Kesinee ; Day, Nicholas P.J. ; Tarning, Joel ; Winterberg, Markus ; White, Nicholas J. ; Llinas, Manuel ; Dondorp, Arjen M. / Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics. In: Journal of Infectious Diseases. 2019 ; Vol. 219, No. 11. pp. 1766-1776.
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abstract = "Background. Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. Methods. A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. Results. We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. Conclusions. These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria.",
author = "Leopold, {Stije J.} and Aniruddha Ghose and Allman, {Erik L.} and Kingston, {Hugh W.F.} and Amir Hossain and Dutta, {Asok Kumar} and Katherine Plewes and Kesinee Chotivanich and Day, {Nicholas P.J.} and Joel Tarning and Markus Winterberg and White, {Nicholas J.} and Manuel Llinas and Dondorp, {Arjen M.}",
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Leopold, SJ, Ghose, A, Allman, EL, Kingston, HWF, Hossain, A, Dutta, AK, Plewes, K, Chotivanich, K, Day, NPJ, Tarning, J, Winterberg, M, White, NJ, Llinas, M & Dondorp, AM 2019, 'Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics', Journal of Infectious Diseases, vol. 219, no. 11, pp. 1766-1776. https://doi.org/10.1093/infdis/jiy727

Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics. / Leopold, Stije J.; Ghose, Aniruddha; Allman, Erik L.; Kingston, Hugh W.F.; Hossain, Amir; Dutta, Asok Kumar; Plewes, Katherine; Chotivanich, Kesinee; Day, Nicholas P.J.; Tarning, Joel; Winterberg, Markus; White, Nicholas J.; Llinas, Manuel; Dondorp, Arjen M.

In: Journal of Infectious Diseases, Vol. 219, No. 11, 01.06.2019, p. 1766-1776.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identifying the Components of Acidosis in Patients with Severe Plasmodium falciparum Malaria Using Metabolomics

AU - Leopold, Stije J.

AU - Ghose, Aniruddha

AU - Allman, Erik L.

AU - Kingston, Hugh W.F.

AU - Hossain, Amir

AU - Dutta, Asok Kumar

AU - Plewes, Katherine

AU - Chotivanich, Kesinee

AU - Day, Nicholas P.J.

AU - Tarning, Joel

AU - Winterberg, Markus

AU - White, Nicholas J.

AU - Llinas, Manuel

AU - Dondorp, Arjen M.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background. Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. Methods. A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. Results. We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. Conclusions. These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria.

AB - Background. Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. Methods. A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. Results. We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. Conclusions. These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria.

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