Antigenic variation and virulence in Plasmodium falciparum malaria : studies on the surface protein PfEMP1
Author: Blomqvist, Karin
Date: 2011-11-04
Location: Hörsal E512, Theorells väg 1, MTC, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
Abstract
Approximately 40% of the world’s population is at risk of contracting malaria, a disease caused by the intracellular protozoan Plasmodium. The species Plasmodium falciparum is responsible for the majority of severe morbidity and mortality. A major virulence factor of the falciparum parasite is its ability to cause accumulation of parasitized red blood cells in the microvasculature of different organs, through binding to endothelial cells (cytoadhesion) and to unparasitized red blood cells (rosetting). The binding is mediated by members of the adhesive surface protein, PfEMP1 (P. falciparum erythrocyte membrane protein 1), which is encoded by the variable var gene family. One var gene is activated at a time and the var gene expression can be switched in order to avoid antibody response, a mechanism called antigenic variation. This makes PfEMP1 pivotal for the virulence of the P. falciparum parasite. The studies presented in this thesis aim at enhancing the understanding of PfEMP1, both at a phenotypic and a genotypic level, with special focus on clinical isolates.
We developed a precise method to study var gene transcription and applied it to elucidate var gene transcription dynamics in clinical isolates from Uganda as well as in laboratory strains. The results show that the var gene transcription profile is unique for each parasite isolate and strain, and that clinical isolates have more complex transcriptional profiles than in vitro strains. Clinical isolates were found to switch away from the var genes associated with severe disease upon in vitro adaptation. We therefore conclude that it is crucial to study var genes directly after parasite collection so that it reflects the expression in the patient. A model parasite clone for severe malaria was used in order to confirm that the method correctly identified the var gene that is transcribed, translated into PfEMP1 and transported to the parasitized red blood cell surface.
Heparan sulfate has been found to be a PfEMP1 receptor that is frequently recognized in clinical isolates. To explore this finding, we generated a low anti-coagulant heparin (LAH) to study its ability to disrupt rosettes in fresh clinical isolates. We found that LAH is able to disrupt rosettes in clinical isolates from children infected with malaria. The rosette disruption effect was more pronounced in isolates from children with complicated malaria than in isolates from children with mild malaria indicating that this compound in the future might have a place in the treatment of severe malaria.
Further, we identified a surface-exposed sequence in PfEMP1, which is associated with severe malaria. The sequence includes a motif that is able to induce a cross-reactive antibody response, in which the generated antibodies recognize parasitized red blood cells in a subset of clinical isolates and laboratory strains. In addition, the antibodies reacted selectively with the sequence motif in a peptide-array of different PfEMP1 domains. Residues within the sequence motif were found to be important for antibody binding, and one third of degenerate peptide-sequences of Ugandan patient isolates were shown to react with the antibody. We conclude that the sequence motif, which is associated with severe malaria, generates strain-transcending antibodies that recognize the parasitized red blood cell surface.
In conclusion, this thesis provides insights into var gene transcription dynamics in clinical isolates, it enhances the understanding of low anticoagulant heparin as a treatment for severe malaria, and it describes a surface-exposed epitope in PfEMP1 associated with severe malaria generating strain-transcending antibodies.
We developed a precise method to study var gene transcription and applied it to elucidate var gene transcription dynamics in clinical isolates from Uganda as well as in laboratory strains. The results show that the var gene transcription profile is unique for each parasite isolate and strain, and that clinical isolates have more complex transcriptional profiles than in vitro strains. Clinical isolates were found to switch away from the var genes associated with severe disease upon in vitro adaptation. We therefore conclude that it is crucial to study var genes directly after parasite collection so that it reflects the expression in the patient. A model parasite clone for severe malaria was used in order to confirm that the method correctly identified the var gene that is transcribed, translated into PfEMP1 and transported to the parasitized red blood cell surface.
Heparan sulfate has been found to be a PfEMP1 receptor that is frequently recognized in clinical isolates. To explore this finding, we generated a low anti-coagulant heparin (LAH) to study its ability to disrupt rosettes in fresh clinical isolates. We found that LAH is able to disrupt rosettes in clinical isolates from children infected with malaria. The rosette disruption effect was more pronounced in isolates from children with complicated malaria than in isolates from children with mild malaria indicating that this compound in the future might have a place in the treatment of severe malaria.
Further, we identified a surface-exposed sequence in PfEMP1, which is associated with severe malaria. The sequence includes a motif that is able to induce a cross-reactive antibody response, in which the generated antibodies recognize parasitized red blood cells in a subset of clinical isolates and laboratory strains. In addition, the antibodies reacted selectively with the sequence motif in a peptide-array of different PfEMP1 domains. Residues within the sequence motif were found to be important for antibody binding, and one third of degenerate peptide-sequences of Ugandan patient isolates were shown to react with the antibody. We conclude that the sequence motif, which is associated with severe malaria, generates strain-transcending antibodies that recognize the parasitized red blood cell surface.
In conclusion, this thesis provides insights into var gene transcription dynamics in clinical isolates, it enhances the understanding of low anticoagulant heparin as a treatment for severe malaria, and it describes a surface-exposed epitope in PfEMP1 associated with severe malaria generating strain-transcending antibodies.
List of papers:
I. var gene transcription dynamics in Plasmodium falciparum patient isolates. Blomqvist Karin*, Normark Johan*, Nilsson Daniel, Ribacke Ulf, Orikiriza Judy, Trillkott Petter, Byarugaba Justus, Egwang Tom, Kironde Fred, Andersson Björn, Wahlgren Mats. Mol Biochem Parasitol. 2010 Apr;170(2):74-83. *These authors contributed equally to this work.
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II. var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.2. Albrecht Letusa, Moll Kirsten, Blomqvist Karin, Normark Johan, Chen Qijun, Wahlgren Mats. Malar J. 2011 Jan 25;10:17.
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III. Low anticoagulant heparin disrupts Plasmodium falciparum rosettes in fresh clinical isolates. Leitgeb Anna*, Blomqvist Karin*, Cho-Ngwa Fidelis, Samje Moses, Nde Peter, Titanji Vincent, Wahlgren Mats. Am J Trop Med Hyg. 2011 Mar;84(3):390-6. *These authors contributed equally to this work.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. A PfEMP1-DBL1 sequence associated with severe Plasmodium falciparum malaria generates strain-transcending antibodies. Blomqvist Karin, Albrecht Letusa, Quintana Pilar, Angeletti Davide, Joannin Nicolas, Chêne Arnaud, Moll Kirsten, Wahlgren Mats. [Manuscript]
I. var gene transcription dynamics in Plasmodium falciparum patient isolates. Blomqvist Karin*, Normark Johan*, Nilsson Daniel, Ribacke Ulf, Orikiriza Judy, Trillkott Petter, Byarugaba Justus, Egwang Tom, Kironde Fred, Andersson Björn, Wahlgren Mats. Mol Biochem Parasitol. 2010 Apr;170(2):74-83. *These authors contributed equally to this work.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.2. Albrecht Letusa, Moll Kirsten, Blomqvist Karin, Normark Johan, Chen Qijun, Wahlgren Mats. Malar J. 2011 Jan 25;10:17.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Low anticoagulant heparin disrupts Plasmodium falciparum rosettes in fresh clinical isolates. Leitgeb Anna*, Blomqvist Karin*, Cho-Ngwa Fidelis, Samje Moses, Nde Peter, Titanji Vincent, Wahlgren Mats. Am J Trop Med Hyg. 2011 Mar;84(3):390-6. *These authors contributed equally to this work.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. A PfEMP1-DBL1 sequence associated with severe Plasmodium falciparum malaria generates strain-transcending antibodies. Blomqvist Karin, Albrecht Letusa, Quintana Pilar, Angeletti Davide, Joannin Nicolas, Chêne Arnaud, Moll Kirsten, Wahlgren Mats. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Wahlgren, Mats
Issue date: 2011-10-17
Rights:
Publication year: 2011
ISBN: 978-91-7457-459-3
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