Cell Reports (Sep 2020)
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
Affiliations
- Guoyue Xu
- 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
- Rebekah van Bruggen
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
- Christian O. Gualtieri
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
- Neda Moradin
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada
- Adrien Fois
- 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
- Diane Vallerand
- Université de Montréal, Département de Pharmacologie et Physiologie, Pav Roger-Gaudry, 2900 Édouard-Montpetit, Montréal, QC H3T 1J4, Canada
- Mariana De Sa Tavares Russo
- Rosalind and Morris Goodman Cancer Research Centre, 1160 Pin Avenue West, Montréal, QC H3A 1A3, Canada
- Angelia Bassenden
- Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
- Wenyun Lu
- Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Mifong Tam
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Sylvie Lesage
- 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
- Hélène Girouard
- Université de Montréal, Département de Pharmacologie et Physiologie, Pav Roger-Gaudry, 2900 Édouard-Montpetit, Montréal, QC H3T 1J4, Canada
- Daina Zofija Avizonis
- Rosalind and Morris Goodman Cancer Research Centre, 1160 Pin Avenue West, Montréal, QC H3A 1A3, Canada
- Geneviève Deblois
- 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
- Josef T. Prchal
- Division of Hematology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA
- Mary Stevenson
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Albert Berghuis
- Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
- Tom Muir
- Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Joshua Rabinowitz
- Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Silvia M. Vidal
- 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
- Nassima Fodil
- 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; Corresponding author
- Philippe Gros
- 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; Corresponding author
- Journal volume & issue
-
Vol. 32,
no. 12
p. 108170
Abstract
Summary: 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.
