The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria
Abstract Background Recent genome wide analysis studies have identified a strong association between single nucleotide variations within the human ATP2B4 gene and susceptibility to severe malaria. The ATP2B4 gene encodes the plasma membrane calcium ATPase 4 (PMCA4), which is responsible for controll...
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doaj-0193d8e284dd47609fc0be6ba801edee2021-07-04T11:44:53ZengBMCMalaria Journal1475-28752021-07-0120111610.1186/s12936-021-03832-wThe plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malariaAna Villegas-Mendez0Nicholas Stafford1Michael J. Haley2Normalita Eka Pravitasari3Florence Baudoin4Adnan Ali5Puji Budi Setia Asih6Josephine E. Siregar7Esther Baena8Din Syafruddin9Kevin N. Couper10Delvac Oceandy11The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of ManchesterDivision of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of ManchesterThe Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of ManchesterEijkman Institute for Molecular BiologyDivision of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of ManchesterCancer Research UK Manchester Institute, The University of ManchesterEijkman Institute for Molecular BiologyEijkman Institute for Molecular BiologyCancer Research UK Manchester Institute, The University of ManchesterEijkman Institute for Molecular BiologyThe Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of ManchesterDivision of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of ManchesterAbstract Background Recent genome wide analysis studies have identified a strong association between single nucleotide variations within the human ATP2B4 gene and susceptibility to severe malaria. The ATP2B4 gene encodes the plasma membrane calcium ATPase 4 (PMCA4), which is responsible for controlling the physiological level of intracellular calcium in many cell types, including red blood cells (RBCs). It is, therefore, postulated that genetic differences in the activity or expression level of PMCA4 alters intracellular Ca2+ levels and affects RBC hydration, modulating the invasion and growth of the Plasmodium parasite within its target host cell. Methods In this study the course of three different Plasmodium spp. infections were examined in mice with systemic knockout of Pmca4 expression. Results Ablation of PMCA4 reduced the size of RBCs and their haemoglobin content but did not affect RBC maturation and reticulocyte count. Surprisingly, knockout of PMCA4 did not significantly alter peripheral parasite burdens or the dynamics of blood stage Plasmodium chabaudi infection or reticulocyte-restricted Plasmodium yoelii infection. Interestingly, although ablation of PMCA4 did not affect peripheral parasite levels during Plasmodium berghei infection, it did promote slight protection against experimental cerebral malaria, associated with a minor reduction in antigen-experienced T cell accumulation in the brain. Conclusions The finding suggests that PMCA4 may play a minor role in the development of severe malarial complications, but that this appears independent of direct effects on parasite invasion, growth or survival within RBCs.https://doi.org/10.1186/s12936-021-03832-wPMCA4MalariaKnockout micePlasmodiumCerebral malariaRed blood cell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Villegas-Mendez Nicholas Stafford Michael J. Haley Normalita Eka Pravitasari Florence Baudoin Adnan Ali Puji Budi Setia Asih Josephine E. Siregar Esther Baena Din Syafruddin Kevin N. Couper Delvac Oceandy |
spellingShingle |
Ana Villegas-Mendez Nicholas Stafford Michael J. Haley Normalita Eka Pravitasari Florence Baudoin Adnan Ali Puji Budi Setia Asih Josephine E. Siregar Esther Baena Din Syafruddin Kevin N. Couper Delvac Oceandy The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria Malaria Journal PMCA4 Malaria Knockout mice Plasmodium Cerebral malaria Red blood cell |
author_facet |
Ana Villegas-Mendez Nicholas Stafford Michael J. Haley Normalita Eka Pravitasari Florence Baudoin Adnan Ali Puji Budi Setia Asih Josephine E. Siregar Esther Baena Din Syafruddin Kevin N. Couper Delvac Oceandy |
author_sort |
Ana Villegas-Mendez |
title |
The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
title_short |
The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
title_full |
The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
title_fullStr |
The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
title_full_unstemmed |
The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
title_sort |
plasma membrane calcium atpase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria |
publisher |
BMC |
series |
Malaria Journal |
issn |
1475-2875 |
publishDate |
2021-07-01 |
description |
Abstract Background Recent genome wide analysis studies have identified a strong association between single nucleotide variations within the human ATP2B4 gene and susceptibility to severe malaria. The ATP2B4 gene encodes the plasma membrane calcium ATPase 4 (PMCA4), which is responsible for controlling the physiological level of intracellular calcium in many cell types, including red blood cells (RBCs). It is, therefore, postulated that genetic differences in the activity or expression level of PMCA4 alters intracellular Ca2+ levels and affects RBC hydration, modulating the invasion and growth of the Plasmodium parasite within its target host cell. Methods In this study the course of three different Plasmodium spp. infections were examined in mice with systemic knockout of Pmca4 expression. Results Ablation of PMCA4 reduced the size of RBCs and their haemoglobin content but did not affect RBC maturation and reticulocyte count. Surprisingly, knockout of PMCA4 did not significantly alter peripheral parasite burdens or the dynamics of blood stage Plasmodium chabaudi infection or reticulocyte-restricted Plasmodium yoelii infection. Interestingly, although ablation of PMCA4 did not affect peripheral parasite levels during Plasmodium berghei infection, it did promote slight protection against experimental cerebral malaria, associated with a minor reduction in antigen-experienced T cell accumulation in the brain. Conclusions The finding suggests that PMCA4 may play a minor role in the development of severe malarial complications, but that this appears independent of direct effects on parasite invasion, growth or survival within RBCs. |
topic |
PMCA4 Malaria Knockout mice Plasmodium Cerebral malaria Red blood cell |
url |
https://doi.org/10.1186/s12936-021-03832-w |
work_keys_str_mv |
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