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 Vidal; Nassima Fodil; Philippe Gros

doi:10.1016/j.celrep.2020.108170

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.

Authors

Guoyue Xu¹, Rebekah van Bruggen², Christian O Gualtieri², Neda Moradin³, Adrien Fois⁴, Diane Vallerand⁵, Mariana De Sa Tavares Russo⁶, Angelia Bassenden⁷, Wenyun Lu⁸, Mifong Tam⁹, Sylvie Lesage⁴, Hélène Girouard⁵, Daina Zofija Avizonis⁶, Geneviève Deblois¹⁰, Josef T Prchal¹¹, Mary Stevenson⁹, Albert Berghuis⁷, Tom Muir¹², Joshua Rabinowitz¹², Silvia M Vidal¹³, Nassima Fodil¹⁴, Philippe Gros¹⁵

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada.
² McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
³ McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada.
⁴ Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3T 1J4, Canada.
⁵ Université de Montréal, Département de Pharmacologie et Physiologie, Pav Roger-Gaudry, 2900 Édouard-Montpetit, Montréal, QC H3T 1J4, Canada.
⁶ Rosalind and Morris Goodman Cancer Research Centre, 1160 Pin Avenue West, Montréal, QC H3A 1A3, Canada.
⁷ Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
⁸ Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
⁹ Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
¹⁰ Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada; Faculté de Pharmacie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹¹ Division of Hematology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
¹² Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
¹³ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
¹⁴ McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Centre CERMO-FC Pavillon des Sciences Biologiques, 141 Avenue du Président Kennedy, Montréal, QC H2X 3Y7, Canada. Electronic address: nassima.fodil@mcgill.ca.
¹⁵ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address: philippe.gros@mcgill.ca.

PMID: 32966787
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 (Bpgm^L166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in Bpgm^L166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of Bpgm^L166P 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

Grants and funding

CIHR/Canada