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2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane

Malaria remains a major world public health problem, contributing to poverty and inequality. It is urgent to find new efficacious tools with few adverse effects. Malaria has selected red blood cell (RBC) alterations linked to resistance against infection, and understanding the protective mechanisms...

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Autores principales: Carvalho, Maria, Medeiros, Márcia M., Morais, Inês, Lopes, Catarina S., Balau, Ana, Santos, Nuno C., Carvalho, Filomena A., Arez, Ana Paula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866842/
https://www.ncbi.nlm.nih.gov/pubmed/36674863
http://dx.doi.org/10.3390/ijms24021336
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author Carvalho, Maria
Medeiros, Márcia M.
Morais, Inês
Lopes, Catarina S.
Balau, Ana
Santos, Nuno C.
Carvalho, Filomena A.
Arez, Ana Paula
author_facet Carvalho, Maria
Medeiros, Márcia M.
Morais, Inês
Lopes, Catarina S.
Balau, Ana
Santos, Nuno C.
Carvalho, Filomena A.
Arez, Ana Paula
author_sort Carvalho, Maria
collection PubMed
description Malaria remains a major world public health problem, contributing to poverty and inequality. It is urgent to find new efficacious tools with few adverse effects. Malaria has selected red blood cell (RBC) alterations linked to resistance against infection, and understanding the protective mechanisms involved may be useful for developing host-directed tools to control Plasmodium infection. Pyruvate kinase deficiency has been associated with resistance to malaria. Pyruvate kinase-deficient RBCs display an increased concentration of 2,3-diphosphoglycerate (2,3-DPG). We recently showed that 2,3-DPG impacts in vitro intraerythrocytic parasite growth, induces a shift of the metabolic profile of infected cells (iRBCs), making it closer to that of noninfected ones (niRBCs), and decreases the number of parasite progenies that invade new RBCs. As an increase of 2,3-DPG content may also have an adverse effect on RBC membrane and, consequently, on the parasite invasion, in this study, we explored modifications of the RBC morphology, biomechanical properties, and RBC membrane on Plasmodium falciparum in vitro cultures treated with 2,3-DPG, using atomic force microscopy (AFM)-based force spectroscopy and other experimental approaches. The presence of infection by P. falciparum significantly increased the rigidity of parasitized cells and influenced the morphology of RBCs, as parasitized cells showed a decrease of the area-to-volume ratio. The extracellular addition of 2,3-DPG also slightly affected the stiffness of niRBCs, making it more similar to that of infected cells. It also changed the niRBC height, making the cells appear more elongated. Moreover, 2,3-DPG treatment influenced the cell surface charge, becoming more negative in treated RBCs than in untreated ones. The results indicate that treatment with 2,3-DPG has only a mild effect on RBCs in comparison with the effect of the presence of the parasite on the host cell. 2,3-DPG is an endogenous host metabolite, which may, in the future, originate a new antimalarial tool with few adverse effects on noninfected cells.
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spelling pubmed-98668422023-01-22 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane Carvalho, Maria Medeiros, Márcia M. Morais, Inês Lopes, Catarina S. Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula Int J Mol Sci Article Malaria remains a major world public health problem, contributing to poverty and inequality. It is urgent to find new efficacious tools with few adverse effects. Malaria has selected red blood cell (RBC) alterations linked to resistance against infection, and understanding the protective mechanisms involved may be useful for developing host-directed tools to control Plasmodium infection. Pyruvate kinase deficiency has been associated with resistance to malaria. Pyruvate kinase-deficient RBCs display an increased concentration of 2,3-diphosphoglycerate (2,3-DPG). We recently showed that 2,3-DPG impacts in vitro intraerythrocytic parasite growth, induces a shift of the metabolic profile of infected cells (iRBCs), making it closer to that of noninfected ones (niRBCs), and decreases the number of parasite progenies that invade new RBCs. As an increase of 2,3-DPG content may also have an adverse effect on RBC membrane and, consequently, on the parasite invasion, in this study, we explored modifications of the RBC morphology, biomechanical properties, and RBC membrane on Plasmodium falciparum in vitro cultures treated with 2,3-DPG, using atomic force microscopy (AFM)-based force spectroscopy and other experimental approaches. The presence of infection by P. falciparum significantly increased the rigidity of parasitized cells and influenced the morphology of RBCs, as parasitized cells showed a decrease of the area-to-volume ratio. The extracellular addition of 2,3-DPG also slightly affected the stiffness of niRBCs, making it more similar to that of infected cells. It also changed the niRBC height, making the cells appear more elongated. Moreover, 2,3-DPG treatment influenced the cell surface charge, becoming more negative in treated RBCs than in untreated ones. The results indicate that treatment with 2,3-DPG has only a mild effect on RBCs in comparison with the effect of the presence of the parasite on the host cell. 2,3-DPG is an endogenous host metabolite, which may, in the future, originate a new antimalarial tool with few adverse effects on noninfected cells. MDPI 2023-01-10 /pmc/articles/PMC9866842/ /pubmed/36674863 http://dx.doi.org/10.3390/ijms24021336 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carvalho, Maria
Medeiros, Márcia M.
Morais, Inês
Lopes, Catarina S.
Balau, Ana
Santos, Nuno C.
Carvalho, Filomena A.
Arez, Ana Paula
2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title_full 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title_fullStr 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title_full_unstemmed 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title_short 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
title_sort 2,3-diphosphoglycerate and the protective effect of pyruvate kinase deficiency against malaria infection—exploring the role of the red blood cell membrane
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866842/
https://www.ncbi.nlm.nih.gov/pubmed/36674863
http://dx.doi.org/10.3390/ijms24021336
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