Differential Gene Expression of Malaria Parasite in Response to Red Blood Cell-Specific Glycolytic Intermediate 2,3-Diphosphoglycerate (2,3-DPG)

Ana Balau, Daniel Sobral, Patrícia Abrantes, Inês Santos, Verónica Mixão, João Paulo Gomes, Sandra Antunes, Ana Paula Arez

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Abstract

Innovative strategies to control malaria are urgently needed. Exploring the interplay between Plasmodium sp. parasites and host red blood cells (RBCs) offers opportunities for novel antimalarial interventions. Pyruvate kinase deficiency (PKD), characterized by heightened 2,3-diphosphoglycerate (2,3-DPG) concentration, has been associated with protection against malaria. Elevated levels of 2,3-DPG, a specific mammalian metabolite, may hinder glycolysis, prompting us to hypothesize its potential contribution to PKD-mediated protection. We investigated the impact of the extracellular supplementation of 2,3-DPG on the Plasmodium falciparum intraerythrocytic developmental cycle in vitro. The results showed an inhibition of parasite growth, resulting from significantly fewer progeny from 2,3-DPG-treated parasites. We analyzed differential gene expression and the transcriptomic profile of P. falciparum trophozoites, from in vitro cultures subjected or not subjected to the action of 2,3-DPG, using Nanopore Sequencing Technology. The presence of 2,3-DPG in the culture medium was associated with the significant differential expression of 71 genes, mostly associated with the GO terms nucleic acid binding, transcription or monoatomic anion channel. Further, several genes related to cell cycle control were downregulated in treated parasites. These findings suggest that the presence of this RBC-specific glycolytic metabolite impacts the expression of genes transcribed during the parasite trophozoite stage and the number of merozoites released from individual schizonts, which supports the potential role of 2,3-DPG in the mechanism of protection against malaria by PKD.

Original languageEnglish
Article number16869
Number of pages16
JournalInternational Journal of Molecular Sciences
Volume24
Issue number23
DOIs
Publication statusPublished - 28 Nov 2023

Keywords

  • Plasmodium falciparum
  • Infection
  • erythrocyte
  • pyruvate kinase deficiency
  • enzymopathy
  • 2,3-bisphosphoglycerate
  • transcriptome
  • nanopore sequencing technology

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