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

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 journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Article number	108170
Journal	Cell Reports
Volume	32
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2020.108170
State	Published - Sep 22 2020

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

Keywords

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

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10.1016/j.celrep.2020.108170

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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), Article 108170. https://doi.org/10.1016/j.celrep.2020.108170

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title = "Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia",

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",

author = "Guoyue Xu and {van Bruggen}, Rebekah and Gualtieri, {Christian O.} and Neda Moradin and Adrien Fois and Diane Vallerand and {De Sa Tavares Russo}, Mariana and Angelia Bassenden and Wenyun Lu and Mifong Tam and Sylvie Lesage and H{\'e}l{\`e}ne Girouard and Avizonis, {Daina Zofija} and Genevi{\`e}ve Deblois and Prchal, {Josef T.} and Mary Stevenson and Albert Berghuis and Tom Muir and Joshua Rabinowitz and Vidal, {Silvia M.} and Nassima Fodil and Philippe Gros",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = sep,

day = "22",

doi = "10.1016/j.celrep.2020.108170",

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Xu, G, van Bruggen, R, Gualtieri, CO, Moradin, N, Fois, A, Vallerand, D, De Sa Tavares Russo, M, Bassenden, A, Lu, W, Tam, M, Lesage, S, Girouard, H, Avizonis, DZ, Deblois, G, Prchal, JT, Stevenson, M, Berghuis, A, Muir, T , Rabinowitz, J, Vidal, SM, Fodil, N & Gros, P 2020, 'Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia', Cell Reports, vol. 32, no. 12, 108170. https://doi.org/10.1016/j.celrep.2020.108170

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T1 - Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia

AU - Xu, Guoyue

AU - van Bruggen, Rebekah

AU - Gualtieri, Christian O.

AU - Moradin, Neda

AU - Fois, Adrien

AU - Vallerand, Diane

AU - De Sa Tavares Russo, Mariana

AU - Bassenden, Angelia

AU - Lu, Wenyun

AU - Tam, Mifong

AU - Lesage, Sylvie

AU - Girouard, Hélène

AU - Avizonis, Daina Zofija

AU - Deblois, Geneviève

AU - Prchal, Josef T.

AU - Stevenson, Mary

AU - Berghuis, Albert

AU - Muir, Tom

AU - Rabinowitz, Joshua

AU - Vidal, Silvia M.

AU - Fodil, Nassima

AU - Gros, Philippe

PY - 2020/9/22

Y1 - 2020/9/22

N2 - 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.

AB - 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.

KW - BPGM

KW - RBC

KW - anemia

KW - cerebral malaria

KW - erythrocyte metabolism

KW - erythrocytosis

KW - erythropoiesis

KW - genetic susceptibility

KW - malaria

KW - polycytemia

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DO - 10.1016/j.celrep.2020.108170

M3 - Article

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AN - SCOPUS:85091373184

SN - 2211-1247

VL - 32

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 108170

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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