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

Cell Rep. 2020 Sep 22;32(12):108170. doi: 10.1016/j.celrep.2020.108170.

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.

Keywords: BPGM; RBC; anemia; cerebral malaria; erythrocyte metabolism; erythrocytosis; erythropoiesis; genetic susceptibility; malaria; polycytemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Anemia / etiology*
  • Anemia / prevention & control*
  • Animals
  • Base Sequence
  • Bisphosphoglycerate Mutase / chemistry
  • Bisphosphoglycerate Mutase / deficiency*
  • Bisphosphoglycerate Mutase / genetics
  • Bisphosphoglycerate Mutase / metabolism
  • Enzyme Stability
  • Erythrocytes / enzymology
  • Erythrocytes / parasitology
  • Erythropoiesis
  • Extracellular Matrix / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Malaria, Cerebral / complications
  • Malaria, Cerebral / enzymology*
  • Malaria, Cerebral / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation / genetics
  • Parasites / growth & development
  • Plasmodium / growth & development
  • Polycythemia

Substances

  • Bisphosphoglycerate Mutase

Grant support