Dataset Information

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 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.

SUBMITTER: Villegas-Mendez A

PROVIDER: S-EPMC8252299 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria.

Villegas-Mendez Ana A Stafford Nicholas N Haley Michael J MJ Pravitasari Normalita Eka NE Baudoin Florence F Ali Adnan A Asih Puji Budi Setia PBS Siregar Josephine E JE Baena Esther E Syafruddin Din D Couper Kevin N KN Oceandy Delvac D

Malaria journal 20210702 1

<h4>Background</h4>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 P ...[more]

PMID: 34215257

Similar Datasets

Project description:Cerebral malaria (CM) is a severe complication of a Plasmodium falciparum infection and is still responsible for a high number of deaths and long term disabilities in children in sub-Saharan Africa. The pathogenesis of this syndrome remains incompletely understood but a number of mechanisms and effectors have been proposed, including plasma microparticles (MP). These submicron vesicles released by potentially all cells carry proteins and nucleic acids derived from the mother cell. In CM, their numbers are increased in patients’ circulation and, in the mouse model, they can be localised within inflamed vessels, suggesting their involvement in vascular damage. In the present work we define, for the first time, the protein cargo of MP during experimental cerebral malaria (ECM) with the overarching hypothesis that characterising this content could help in better understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected mice and mice infected with P. berghei ANKA at two different stages of infection, i.e., pre-clinical phase and full blown syndrome. Overall, we identified 368 proteins, 60 of which were differentially expressed, as determined by quantitative comparison using the TMT® isobaric labelling. The analysis with Ingenuity® IPA highlighted important networks significantly represented among the proteins over-expressed (n=42) or identified only (n=21) in ECM, comprising mechanisms already proposed to be involved in CM, such as endothelial activation. Two proteins of interest, carbonic anhydrase I (CA-I) and S100A8, were verified by western blot on newly collected MP samples from DBA/1 (n=16) and C57BL/6 (n=8) mice, and confirmed to be associated with ECM MP. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis. The identification of the cellular source of MP containing proteins associated to the disease state will contribute to further understanding their involvement in CM.

Dataset Information

The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria.

Background

Methods

Results

Conclusions

Publications

The plasma membrane calcium ATPase 4 does not influence parasite levels but partially promotes experimental cerebral malaria during murine blood stage malaria.

Similar Datasets

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