Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults
Abstract Background Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown. Methods Using a recall-by-genotype design, we investigat...
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ftdoajarticles:oai:doaj.org/article:d03129fdaa8f4f0ca3785c34c9916e72 2023-06-18T03:39:41+02:00 Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults Fatou Joof Elena Hartmann Alison Jarvis Alhassan Colley James H. Cross Marion Avril Andrew M. Prentice Carla Cerami 2023-01-01T00:00:00Z https://doi.org/10.1186/s12936-022-04359-4 https://doaj.org/article/d03129fdaa8f4f0ca3785c34c9916e72 EN eng BMC https://doi.org/10.1186/s12936-022-04359-4 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-022-04359-4 1475-2875 https://doaj.org/article/d03129fdaa8f4f0ca3785c34c9916e72 Malaria Journal, Vol 22, Iss 1, Pp 1-11 (2023) Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2023 ftdoajarticles https://doi.org/10.1186/s12936-022-04359-4 2023-06-04T00:40:36Z Abstract Background Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown. Methods Using a recall-by-genotype design, we investigated the impact of a common haplotype variant in ATP2B4 using in vitro assays that model erythrocyte stage malaria pathogenesis. Ninety-six donors representing homozygotes (carriers of the minor alleles, T/T (variant), heterozygote T/C and wildtype C/C (ancestral)) carriers of the tagging SNP rs1541252 were selected from a cohort of over 12,000 participants in the Keneba Biobank. Results Red blood cells (RBCs) from homozygotes showed reduced PMCA4b protein expression (mean fluorescence intensities (MFI = 2428 ± 124, 3544 ± 159 and 4261 ± 283], for homozygotes, heterozygotes and wildtypes respectively, p < 0.0001) and slower rates of calcium expulsion (calcium t½ ± SD = 4.7 ± 0.5, 1.8 ± 0.3 and 1.9 ± 0.4 min, p < 0.0001). Growth of a Plasmodium falciparum laboratory strain (FCR3) and two Gambian field isolates was decreased in RBCs from homozygotes compared to heterozygotes and wildtypes (p < 0.01). Genotype group did not affect parasite adhesion in vitro or var-gene expression in malaria-infected RBCs. Parasite growth was inhibited by a known inhibitor of PMCA4b, aurintricarboxylic acid (IC50 = 122uM CI: 110–134) confirming its sensitivity to calcium channel blockade. Conclusion The data support the hypothesis that this ATP2B4 genotype, common in The Gambia and other malaria-endemic areas, protects against severe malaria through the suppression of parasitaemia during an infection. Reduction in parasite density plays a pivotal role in disease outcome by minimizing all aspects of malaria pathogenesis. Follow up studies are needed to further elucidate the mechanism of protection and to determine if this ATP2B4 genotype carries a fitness cost or increases susceptibility to other human disease. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 22 1 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Fatou Joof Elena Hartmann Alison Jarvis Alhassan Colley James H. Cross Marion Avril Andrew M. Prentice Carla Cerami Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown. Methods Using a recall-by-genotype design, we investigated the impact of a common haplotype variant in ATP2B4 using in vitro assays that model erythrocyte stage malaria pathogenesis. Ninety-six donors representing homozygotes (carriers of the minor alleles, T/T (variant), heterozygote T/C and wildtype C/C (ancestral)) carriers of the tagging SNP rs1541252 were selected from a cohort of over 12,000 participants in the Keneba Biobank. Results Red blood cells (RBCs) from homozygotes showed reduced PMCA4b protein expression (mean fluorescence intensities (MFI = 2428 ± 124, 3544 ± 159 and 4261 ± 283], for homozygotes, heterozygotes and wildtypes respectively, p < 0.0001) and slower rates of calcium expulsion (calcium t½ ± SD = 4.7 ± 0.5, 1.8 ± 0.3 and 1.9 ± 0.4 min, p < 0.0001). Growth of a Plasmodium falciparum laboratory strain (FCR3) and two Gambian field isolates was decreased in RBCs from homozygotes compared to heterozygotes and wildtypes (p < 0.01). Genotype group did not affect parasite adhesion in vitro or var-gene expression in malaria-infected RBCs. Parasite growth was inhibited by a known inhibitor of PMCA4b, aurintricarboxylic acid (IC50 = 122uM CI: 110–134) confirming its sensitivity to calcium channel blockade. Conclusion The data support the hypothesis that this ATP2B4 genotype, common in The Gambia and other malaria-endemic areas, protects against severe malaria through the suppression of parasitaemia during an infection. Reduction in parasite density plays a pivotal role in disease outcome by minimizing all aspects of malaria pathogenesis. Follow up studies are needed to further elucidate the mechanism of protection and to determine if this ATP2B4 genotype carries a fitness cost or increases susceptibility to other human disease. |
format |
Article in Journal/Newspaper |
author |
Fatou Joof Elena Hartmann Alison Jarvis Alhassan Colley James H. Cross Marion Avril Andrew M. Prentice Carla Cerami |
author_facet |
Fatou Joof Elena Hartmann Alison Jarvis Alhassan Colley James H. Cross Marion Avril Andrew M. Prentice Carla Cerami |
author_sort |
Fatou Joof |
title |
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
title_short |
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
title_full |
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
title_fullStr |
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
title_full_unstemmed |
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults |
title_sort |
genetic variations in human atp2b4 gene alter plasmodium falciparum in vitro growth in rbcs from gambian adults |
publisher |
BMC |
publishDate |
2023 |
url |
https://doi.org/10.1186/s12936-022-04359-4 https://doaj.org/article/d03129fdaa8f4f0ca3785c34c9916e72 |
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Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 22, Iss 1, Pp 1-11 (2023) |
op_relation |
https://doi.org/10.1186/s12936-022-04359-4 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-022-04359-4 1475-2875 https://doaj.org/article/d03129fdaa8f4f0ca3785c34c9916e72 |
op_doi |
https://doi.org/10.1186/s12936-022-04359-4 |
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Malaria Journal |
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22 |
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1 |
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1769004397496369152 |