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Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population
Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise,...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677815/ https://www.ncbi.nlm.nih.gov/pubmed/26658699 http://dx.doi.org/10.1371/journal.pone.0144555 |
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author | van Bruggen, Rebekah Gualtieri, Christian Iliescu, Alexandra Louicharoen Cheepsunthorn, Chalisa Mungkalasut, Punchalee Trape, Jean-François Modiano, David Sodiomon Sirima, Bienvenu Singhasivanon, Pratap Lathrop, Mark Sakuntabhai, Anavaj Bureau, Jean-François Gros, Philippe |
author_facet | van Bruggen, Rebekah Gualtieri, Christian Iliescu, Alexandra Louicharoen Cheepsunthorn, Chalisa Mungkalasut, Punchalee Trape, Jean-François Modiano, David Sodiomon Sirima, Bienvenu Singhasivanon, Pratap Lathrop, Mark Sakuntabhai, Anavaj Bureau, Jean-François Gros, Philippe |
author_sort | van Bruggen, Rebekah |
collection | PubMed |
description | Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria. |
format | Online Article Text |
id | pubmed-4677815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46778152015-12-31 Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population van Bruggen, Rebekah Gualtieri, Christian Iliescu, Alexandra Louicharoen Cheepsunthorn, Chalisa Mungkalasut, Punchalee Trape, Jean-François Modiano, David Sodiomon Sirima, Bienvenu Singhasivanon, Pratap Lathrop, Mark Sakuntabhai, Anavaj Bureau, Jean-François Gros, Philippe PLoS One Research Article Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria. Public Library of Science 2015-12-14 /pmc/articles/PMC4677815/ /pubmed/26658699 http://dx.doi.org/10.1371/journal.pone.0144555 Text en © 2015 van Bruggen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article van Bruggen, Rebekah Gualtieri, Christian Iliescu, Alexandra Louicharoen Cheepsunthorn, Chalisa Mungkalasut, Punchalee Trape, Jean-François Modiano, David Sodiomon Sirima, Bienvenu Singhasivanon, Pratap Lathrop, Mark Sakuntabhai, Anavaj Bureau, Jean-François Gros, Philippe Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title | Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title_full | Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title_fullStr | Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title_full_unstemmed | Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title_short | Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population |
title_sort | modulation of malaria phenotypes by pyruvate kinase (pklr) variants in a thai population |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677815/ https://www.ncbi.nlm.nih.gov/pubmed/26658699 http://dx.doi.org/10.1371/journal.pone.0144555 |
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