Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia

Guoyue Xu, Rebekah van Bruggen, Christian O. Gualtieri, Neda Moradin, Adrien Fois, Diane Vallerand, Mariana De Sa Tavares Russo, Angelia Bassenden, Wenyun Lu, Mifong Tam, Sylvie Lesage, Hélène Girouard, Daina Zofija Avizonis, Geneviève Deblois, Josef T. Prchal, Mary Stevenson, Albert Berghuis, Tom Muir, Joshua Rabinowitz, Silvia M. VidalNassima Fodil, Philippe Gros

Research output: Contribution to journalArticle

Abstract

The replication cycle and pathogenesis of the Plasmodium malarial parasite involves rapid expansion in red blood cells (RBCs), and variants of certain RBC-specific proteins protect against malaria in humans. In RBCs, bisphosphoglycerate mutase (BPGM) acts as a key allosteric regulator of hemoglobin/oxyhemoglobin. We demonstrate here that a loss-of-function mutation in the murine Bpgm (BpgmL166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in BpgmL166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of BpgmL166P involves a dual mechanism that enhances the host's stress erythroid response to Plasmodium-driven RBC loss and simultaneously alters the intracellular milieu of the RBCs, including increased oxyhemoglobin and reduced energy metabolism, reducing Plasmodium maturation, and replication. Overall, our study highlights the importance of BPGM as a regulator of hemoglobin/oxyhemoglobin in malaria pathogenesis and suggests a new potential malaria therapeutic target.

Original languageEnglish (US)
Article number108170
JournalCell Reports
Volume32
Issue number12
DOIs
StatePublished - Sep 22 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • BPGM
  • RBC
  • anemia
  • cerebral malaria
  • erythrocyte metabolism
  • erythrocytosis
  • erythropoiesis
  • genetic susceptibility
  • malaria
  • polycytemia

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  • Cite this

    Xu, G., van Bruggen, R., Gualtieri, C. O., Moradin, N., Fois, A., Vallerand, D., De Sa Tavares Russo, M., Bassenden, A., Lu, W., Tam, M., Lesage, S., Girouard, H., Avizonis, D. Z., Deblois, G., Prchal, J. T., Stevenson, M., Berghuis, A., Muir, T., Rabinowitz, J., ... Gros, P. (2020). Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia. Cell Reports, 32(12), [108170]. https://doi.org/10.1016/j.celrep.2020.108170