Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria.
Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by stat...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-11-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1006011 |
| _version_ | 1818738456399970304 |
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| author | Ariel Magallón-Tejada Sónia Machevo Pau Cisteró Thomas Lavstsen Pedro Aide Mercedes Rubio Alfons Jiménez Louise Turner Aida Valmaseda Himanshu Gupta Briegel De Las Salas Inacio Mandomando Christian W Wang Jens E V Petersen Jose Muñoz Joaquim Gascón Eusebio Macete Pedro L Alonso Chetan E Chitnis Quique Bassat Alfredo Mayor |
| author_facet | Ariel Magallón-Tejada Sónia Machevo Pau Cisteró Thomas Lavstsen Pedro Aide Mercedes Rubio Alfons Jiménez Louise Turner Aida Valmaseda Himanshu Gupta Briegel De Las Salas Inacio Mandomando Christian W Wang Jens E V Petersen Jose Muñoz Joaquim Gascón Eusebio Macete Pedro L Alonso Chetan E Chitnis Quique Bassat Alfredo Mayor |
| author_sort | Ariel Magallón-Tejada |
| collection | DOAJ |
| description | Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction. |
| first_indexed | 2024-12-18T01:09:14Z |
| format | Article |
| id | doaj.art-7afdf743e8a74fd8b85d512e6e5e00b9 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-18T01:09:14Z |
| publishDate | 2016-11-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-7afdf743e8a74fd8b85d512e6e5e00b92022-12-21T21:26:10ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-11-011211e100601110.1371/journal.ppat.1006011Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria.Ariel Magallón-TejadaSónia MachevoPau CisteróThomas LavstsenPedro AideMercedes RubioAlfons JiménezLouise TurnerAida ValmasedaHimanshu GuptaBriegel De Las SalasInacio MandomandoChristian W WangJens E V PetersenJose MuñozJoaquim GascónEusebio MacetePedro L AlonsoChetan E ChitnisQuique BassatAlfredo MayorCytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction.https://doi.org/10.1371/journal.ppat.1006011 |
| spellingShingle | Ariel Magallón-Tejada Sónia Machevo Pau Cisteró Thomas Lavstsen Pedro Aide Mercedes Rubio Alfons Jiménez Louise Turner Aida Valmaseda Himanshu Gupta Briegel De Las Salas Inacio Mandomando Christian W Wang Jens E V Petersen Jose Muñoz Joaquim Gascón Eusebio Macete Pedro L Alonso Chetan E Chitnis Quique Bassat Alfredo Mayor Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. PLoS Pathogens |
| title | Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. |
| title_full | Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. |
| title_fullStr | Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. |
| title_full_unstemmed | Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. |
| title_short | Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. |
| title_sort | cytoadhesion to gc1qr through plasmodium falciparum erythrocyte membrane protein 1 in severe malaria |
| url | https://doi.org/10.1371/journal.ppat.1006011 |
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