Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia
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 he...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720311591 |
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doaj-262bb3d083ec462590385e23ff946934 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia Cell Reports malaria BPGM RBC erythropoiesis cerebral malaria anemia |
| author_facet |
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 |
| author_sort |
Guoyue Xu |
| title |
Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia |
| title_short |
Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia |
| title_full |
Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia |
| title_fullStr |
Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia |
| title_full_unstemmed |
Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia |
| title_sort |
bisphosphoglycerate mutase deficiency protects against cerebral malaria and severe malaria-induced anemia |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2020-09-01 |
| description |
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. |
| topic |
malaria BPGM RBC erythropoiesis cerebral malaria anemia |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124720311591 |
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1724583449787891712 |
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doaj-262bb3d083ec462590385e23ff9469342020-11-25T03:28:33ZengElsevierCell Reports2211-12472020-09-013212108170Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced AnemiaGuoyue Xu0Rebekah van Bruggen1Christian O. Gualtieri2Neda Moradin3Adrien Fois4Diane Vallerand5Mariana De Sa Tavares Russo6Angelia Bassenden7Wenyun Lu8Mifong Tam9Sylvie Lesage10Hélène Girouard11Daina Zofija Avizonis12Geneviève Deblois13Josef T. Prchal14Mary Stevenson15Albert Berghuis16Tom Muir17Joshua Rabinowitz18Silvia M. Vidal19Nassima Fodil20Philippe Gros21Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, CanadaMcGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, CanadaMcGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, CanadaMcGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3G 0B1, CanadaImmunology-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, CanadaUniversité de Montréal, Département de Pharmacologie et Physiologie, Pav Roger-Gaudry, 2900 Édouard-Montpetit, Montréal, QC H3T 1J4, CanadaRosalind and Morris Goodman Cancer Research Centre, 1160 Pin Avenue West, Montréal, QC H3A 1A3, CanadaDepartment of Biochemistry, McGill University, Montreal, QC H3A 1A3, CanadaLewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USADepartment of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, CanadaImmunology-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, CanadaUniversité de Montréal, Département de Pharmacologie et Physiologie, Pav Roger-Gaudry, 2900 Édouard-Montpetit, Montréal, QC H3T 1J4, CanadaRosalind and Morris Goodman Cancer Research Centre, 1160 Pin Avenue West, Montréal, QC H3A 1A3, CanadaInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada; Faculté de Pharmacie, Université de Montréal, Montréal, QC H3C 3J7, CanadaDivision of Hematology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USADepartment of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, CanadaDepartment of Biochemistry, McGill University, Montreal, QC H3A 1A3, CanadaLewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USALewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USADepartment 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, CanadaMcGill 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 authorDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720311591malariaBPGMRBCerythropoiesiscerebral malariaanemia |