Dataset Information

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

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. CLINICAL TRIALS REGISTRATION:NCT02451904.

SUBMITTER: Leopold SJ

PROVIDER: S-EPMC6500555 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Leopold Stije J SJ Ghose Aniruddha A Allman Erik L EL Kingston Hugh W F HWF Hossain Amir A Dutta Asok Kumar AK Plewes Katherine K Chotivanich Kesinee K Day Nicholas P J NPJ Tarning Joel J Winterberg Markus M White Nicholas J NJ Llinás Manuel M Dondorp Arjen M AM

The Journal of infectious diseases 20190501 11

<h4>Background</h4>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.<h4>Methods</h4>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 usin ...[more]

PMID: 30566600

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Project description:BACKGROUND: Plasmodium falciparum exports proteins that remodel the erythrocyte membrane. One such protein, called Pf155/RESA (RESA1) contributes to parasite fitness, optimizing parasite survival during febrile episodes. Resa1 gene is a member of a small family comprising three highly related genes. Preliminary evidence led to a search for clues indicating the involvement of RESA2 protein in the pathophysiology of malaria. In the present study, cDNA sequence of resa2 gene was obtained from two different strains. The proportion of P. falciparum isolates having a non-stop T1526C mutation in resa2 gene was evaluated and the association of this genotype with severity of malaria was investigated. METHODS: Resa2 cDNAs of two different strains (a patient isolate and K1 culture adapted strain) was obtained by RT-PCR and DNA sequencing was performed to confirm its gene structure. The proportion of isolates having a T1526C mutation was evaluated using a PCR-RFLP methodology on groups of severe malaria and uncomplicated patients recruited in 1991-1994 in Senegal and in 2009 in Benin. RESULTS: A unique ORF with an internal translation stop was found in the patient isolate (Genbank access number : JN183870), while the K1 strain harboured the T1526C mutation (Genbank access number : JN183869) which affects the internal stop codon and restores a full length coding sequence. About 14% of isolates obtained from Senegal and Benin harboured mutant T1526C parasites. Some isolates had both wild and mutant resa alleles. The analysis excluding those mixed isolates showed that the resa2 T1526C mutation was found more frequently in severe malaria cases than in uncomplicated cases (p?=?0.008). The association of the presence of the mutant allele and parasitaemia >4% was shown in multivariate analysis (p?=?0.03) in the group of Beninese children. CONCLUSIONS: All T1526C mutant parasites theoretically have the ability to give rise to a full-length RESA2 protein. This study raises the hypothesis that the RESA2 protein could favour high-density infections. Other studies in various geographic settings and probably including more patients are now required to replicate these results and to answer the questions raised by these results.

Dataset Information

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

Publications

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

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