Publication
2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane
| Summary: | 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. |
|---|---|
| Main Authors: | Carvalho, Maria |
| Other Authors: | Medeiros, Márcia M.; Morais, Inês; Lopes, Catarina; Balau, Ana; Santos, Nuno C.; Carvalho, Filomena A.; Arez, Ana Paula |
| Subject: | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| Year: | 2023 |
| Country: | Portugal |
| Document type: | article |
| Access type: | open access |
| Associated institution: | Universidade Nova de Lisboa |
| Language: | English |
| Origin: | Repositório Institucional da UNL |
| _version_ | 1868983658875977728 |
|---|---|
| author | Carvalho, Maria |
| author2 | Medeiros, Márcia M. Morais, Inês Lopes, Catarina Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula |
| author2_role | author author author author author author author |
| author_facet | Carvalho, Maria Medeiros, Márcia M. Morais, Inês Lopes, Catarina Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula |
| author_role | author |
| contributor_name_str_mv | Vector borne diseases and pathogens (VBD) Global Health and Tropical Medicine (GHTM) Instituto de Higiene e Medicina Tropical (IHMT) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Carvalho, Maria\"},{\"Person.name\":\"Medeiros, Márcia M.\"},{\"Person.name\":\"Morais, Inês\"},{\"Person.name\":\"Lopes, Catarina\"},{\"Person.name\":\"Balau, Ana\"},{\"Person.name\":\"Santos, Nuno C.\"},{\"Person.name\":\"Carvalho, Filomena A.\"},{\"Person.name\":\"Arez, Ana Paula\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Vector borne diseases and pathogens (VBD) Global Health and Tropical Medicine (GHTM) Instituto de Higiene e Medicina Tropical (IHMT) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| datacite.creators.creator.creatorName.fl_str_mv | Carvalho, Maria Medeiros, Márcia M. Morais, Inês Lopes, Catarina Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula |
| datacite.date.Accepted.fl_str_mv | 2023-01-10T00:00:00Z |
| datacite.date.available.fl_str_mv | 2023-02-14T22:21:04Z |
| datacite.date.embargoed.fl_str_mv | 2023-02-14T22:21:04Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| datacite.titles.title.fl_str_mv | 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane |
| dc.contributor.none.fl_str_mv | Vector borne diseases and pathogens (VBD) Global Health and Tropical Medicine (GHTM) Instituto de Higiene e Medicina Tropical (IHMT) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| dc.creator.none.fl_str_mv | Carvalho, Maria Medeiros, Márcia M. Morais, Inês Lopes, Catarina Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula |
| dc.date.Accepted.fl_str_mv | 2023-01-10T00:00:00Z |
| dc.date.available.fl_str_mv | 2023-02-14T22:21:04Z |
| dc.date.embargoed.fl_str_mv | 2023-02-14T22:21:04Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10362/149210 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| dc.title.fl_str_mv | 2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell Membrane |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| 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. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://run.unl.pt/bitstreams/fbb9c337-f145-4579-b2ee-8f2988b856e9/download |
| id | run_e6830de147d9c242ccbb8e4e70e60676 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10362/149210 |
| inst_facet_str | urn:organizationAcronym:unl{{{_:::_}}}Universidade Nova de Lisboa |
| instacron_str | unl |
| institution | Universidade Nova de Lisboa |
| instname_str | Universidade Nova de Lisboa |
| language | eng |
| network_acronym_str | run |
| network_name_str | Repositório Institucional da UNL |
| oai_identifier_str | oai:run.unl.pt:10362/149210 |
| organization_str_mv | urn:organizationAcronym:unl |
| person_str_mv | Carvalho, Maria Medeiros, Márcia M. Morais, Inês Lopes, Catarina Balau, Ana Santos, Nuno C. Carvalho, Filomena A. Arez, Ana Paula |
| publishDate | 2023 |
| repo_facet_str | urn:repositoryAcronym:run{{{_:::_}}}Repositório Institucional da UNL |
| reponame_str | Repositório Institucional da UNL |
| repository_id_str | urn:repositoryAcronym:run |
| service_str_mv | urn:repositoryAcronym:run |
| spelling | engenMalaria 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.application/pdfen2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection—Exploring the Role of the Red Blood Cell MembraneCarvalho, MariaMedeiros, Márcia M.Morais, InêsLopes, CatarinaBalau, AnaSantos, Nuno C.Carvalho, Filomena A.Arez, Ana PaulaVector borne diseases and pathogens (VBD)Global Health and Tropical Medicine (GHTM)Instituto de Higiene e Medicina Tropical (IHMT)MDPI - Multidisciplinary Digital Publishing InstituteHostingInstitutionOrganizationalRUNe-mailmailto:run@unl.ptrun@unl.ptISSNIsPartOf1422-0067URNIsPartOfPURE: 50793990URNIsPartOfPURE UUID: ea43cf4a-00ab-46ac-b3f1-c1fb81fbeb4bURNIsPartOfORCID: /0000-0002-0497-6532/work/126264016URNIsPartOfScopus: 85146751827URNIsPartOfWOS: WOS:000915364900001URNIsPartOfORCID: /0000-0002-5364-9087/work/177280817DOIIsPartOf10.3390/ijms240213362023-02-14T22:21:04Z2023-01-102023-01-10T00:00:00ZHandlehttp://hdl.handle.net/10362/149210http://purl.org/coar/access_right/c_abf2open accessmalaria2,3-diphosphoglyceratered blood cellerythrocytemorphologyMembrane propertiesSDG 1 - No PovertySDG 3 - Good Health and Well-beingSDG 10 - Reduced Inequalities4198457 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://run.unl.pt/bitstreams/fbb9c337-f145-4579-b2ee-8f2988b856e9/download |
| spellingShingle | 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 malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| status | SINGLETON |
| subject.fl_str_mv | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| 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 | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| topic_facet | malaria 2,3-diphosphoglycerate red blood cell erythrocyte morphology Membrane properties SDG 1 - No Poverty SDG 3 - Good Health and Well-being SDG 10 - Reduced Inequalities |
| url | http://hdl.handle.net/10362/149210 |
| visible | 1 |