@article{bc9ebbadf0af4b73bd381c34e5cc72b9,
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 = "Funding Information: This work was supported by a foundation research grant to P.G. from the Canadian Institutes of Health Research and from the Canadian Institute for Advanced Research (Human and the Microbiome Program). P.G. receives salary support from a Distinguished James McGill Professorship Award. S.L. is an FRQ-S Research Scholars Emeritus awardee. A.F. holds a scholarship from the D{\'e}partement de Microbiologie, Infectiologie et Immunologie at the University of Montr{\'e}al. Metabolite profiling was carried out at the Goodman Cancer Research Center's Metabolomics Innovation Resource, which is funded in part by the Dr. John R. and Clara M. Fraser Memorial Trust, the Terry Fox Foundation, the Qu{\'e}bec Breast Cancer Foundation, and McGill University. The authors are indebted to Susan Gauthier and Genevi{\`e}ve Perreault (McGill University) for expert technical assistance; to Tatiana Scorza (Universit{\'e}) for valuable discussions; and to Kevin Kain (University of Toronto), Georges E. Rivard (Ste-Justine Hospital), and Maria J. Polyak (McGill University) for expert advice and assistance. R.V.B. and C.O.G. contributed to the identification of the ENU-induced mutations. N.M. performed the Evans blue dye extravasation assay. A.F. S.L. D.V. H.G. J.T.P. and N.F. contributed to the blood gas analysis. J.T.P. contributed to the concept, guided the p50 analysis, and edited the manuscript. N.F. M.T.R. and D.Z.A. contributed to the metabolomic analysis. N.F. and G.D. analyzed the metabolomic dataset. All of the protein modeling was done by A. Bassenden and A. Berghuis. N.F. W.L. J.R. and T.M. contributed to the liquid chromatography-mass spectrometry (LC-MS) data. N.F. M.T. and M.S. provided guidance on the mouse models of blood-stage malaria and the study of RBC precursors. S.M.V. and P.G. designed and supervised the ENU-mutagenesis screens. G.X. performed all of the other steady-state, PbA, PcA, and PHZ experiments. The analysis and figures were done by G.X. and N.F. G.X. N.F. and P.G. wrote the manuscript. All of the authors provided helpful comments. The authors declare no competing interests. Funding Information: This work was supported by a foundation research grant to P.G. from the Canadian Institutes of Health Research and from the Canadian Institute for Advanced Research (Human and the Microbiome Program ). P.G. receives salary support from a Distinguished James McGill Professorship Award . S.L. is an FRQ-S Research Scholars Emeritus awardee. A.F. holds a scholarship from the D{\'e}partement de Microbiologie, Infectiologie et Immunologie at the University of Montr{\'e}al . Metabolite profiling was carried out at the Goodman Cancer Research Center{\textquoteright}s Metabolomics Innovation Resource, which is funded in part by the Dr. John R. and Clara M. Fraser Memorial Trust , the Terry Fox Foundation , the Qu{\'e}bec Breast Cancer Foundation , and McGill University . The authors are indebted to Susan Gauthier and Genevi{\`e}ve Perreault (McGill University) for expert technical assistance; to Tatiana Scorza (Universit{\'e}) for valuable discussions; and to Kevin Kain (University of Toronto), Georges E. Rivard (Ste-Justine Hospital), and Maria J. Polyak (McGill University) for expert advice and assistance. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = sep,
day = "22",
doi = "10.1016/j.celrep.2020.108170",
language = "English (US)",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}