α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes

Michael A. Krause, Seidina A S Diakite, Tatiana M. Lopera-Mesa, Chanaki Amaratunga, Takayuki Arie, Karim Traore, Saibou Doumbia, Drissa Konate, Jeffrey Keefer, Mahamadou Diakite, Rick M. Fairhurst

Research output: Contribution to journalArticle

Abstract

Background: α-thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α2β2) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-α/αα) and homozygous (-α/-α) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes - two interactions that are centrally involved in the pathogenesis of severe disease. Methods and Findings: We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect αα/αα (normal), -α/αα and -α/-α RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized -α/αα, -α/-α and -/-α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Conclusions: Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism.

Original languageEnglish (US)
Article numbere37214
JournalPLoS One
Volume7
Issue number5
DOIs
StatePublished - May 18 2012

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thalassemia
Thalassemia
Plasmodium falciparum
cell adhesion
Blood
erythrocytes
Erythrocytes
Endothelial cells
malaria
Malaria
Monocytes
Globins
Endothelial Cells
monocytes
endothelial cells
Membrane Proteins
Parasites
Hemoglobins
membrane proteins
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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Krause, M. A., Diakite, S. A. S., Lopera-Mesa, T. M., Amaratunga, C., Arie, T., Traore, K., ... Fairhurst, R. M. (2012). α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes. PLoS One, 7(5), [e37214]. https://doi.org/10.1371/journal.pone.0037214

α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes. / Krause, Michael A.; Diakite, Seidina A S; Lopera-Mesa, Tatiana M.; Amaratunga, Chanaki; Arie, Takayuki; Traore, Karim; Doumbia, Saibou; Konate, Drissa; Keefer, Jeffrey; Diakite, Mahamadou; Fairhurst, Rick M.

In: PLoS One, Vol. 7, No. 5, e37214, 18.05.2012.

Research output: Contribution to journalArticle

Krause, MA, Diakite, SAS, Lopera-Mesa, TM, Amaratunga, C, Arie, T, Traore, K, Doumbia, S, Konate, D, Keefer, J, Diakite, M & Fairhurst, RM 2012, 'α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes', PLoS One, vol. 7, no. 5, e37214. https://doi.org/10.1371/journal.pone.0037214
Krause MA, Diakite SAS, Lopera-Mesa TM, Amaratunga C, Arie T, Traore K et al. α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes. PLoS One. 2012 May 18;7(5). e37214. https://doi.org/10.1371/journal.pone.0037214
Krause, Michael A. ; Diakite, Seidina A S ; Lopera-Mesa, Tatiana M. ; Amaratunga, Chanaki ; Arie, Takayuki ; Traore, Karim ; Doumbia, Saibou ; Konate, Drissa ; Keefer, Jeffrey ; Diakite, Mahamadou ; Fairhurst, Rick M. / α-thalassemia impairs the cytoadherence of plasmodium falciparum-infected erythrocytes. In: PLoS One. 2012 ; Vol. 7, No. 5.
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AU - Amaratunga, Chanaki

AU - Arie, Takayuki

AU - Traore, Karim

AU - Doumbia, Saibou

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N2 - Background: α-thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α2β2) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-α/αα) and homozygous (-α/-α) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes - two interactions that are centrally involved in the pathogenesis of severe disease. Methods and Findings: We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect αα/αα (normal), -α/αα and -α/-α RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized -α/αα, -α/-α and -/-α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Conclusions: Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism.

AB - Background: α-thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α2β2) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-α/αα) and homozygous (-α/-α) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes - two interactions that are centrally involved in the pathogenesis of severe disease. Methods and Findings: We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect αα/αα (normal), -α/αα and -α/-α RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized -α/αα, -α/-α and -/-α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Conclusions: Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism.

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