Mechanistic Studies of the Negative Epistatic Malaria-protective Interaction Between Sickle Cell Trait and α+thalassemia.
Opi DH., Ochola LB., Tendwa M., Siddondo BR., Ocholla H., Fanjo H., Ghumra A., Ferguson DJP., Rowe JA., Williams TN.
BACKGROUND: Individually, the red blood cell (RBC) polymorphisms sickle cell trait (HbAS) and α+thalassemia protect against severePlasmodium falciparummalaria. It has been shown through epidemiological studies that the co-inheritance of both conditions results in a loss of the protection afforded by each, but the biological mechanisms remain unknown. METHODS: We used RBCs from >300 donors of various HbAS and α+thalassemia genotype combinations to study the individual and combinatorial effects of these polymorphisms on a range of putativeP. falciparumvirulence phenotypesin-vitro, using four well-characterisedP. falciparumlaboratory strains. We studied cytoadhesion of parasitized RBCs (pRBCs) to the endothelial receptors CD36 and ICAM1, rosetting of pRBCs with uninfected RBCs, and pRBC surface expression of the parasite-derived adhesion moleculeP. falciparumErythrocyte Membrane Protein-1 (PfEMP1). FINDINGS: We confirmed previous reports that HbAS pRBCs show reduced cytoadhesion, rosetting and PfEMP1 expression levels compared to normal pRBC controls. Furthermore, we found that co-inheritance of HbAS with α+thalassemia consistently reversed these effects, such that pRBCs of mixed genotype showed levels of cytoadhesion, rosetting and PfEMP1 expression indistinguishable from those seen in normal pRBCs. However, pRBCs with α+thalassemia alone showed parasite strain-specific effects on adhesion, and no consistent reduction in PfEMP1 expression. INTERPRETATION: Our data support the hypothesis that the negative epistasis between HbAS and α+thalassemia observed in epidemiological studies might be explained by host genotype-specific changes in the pRBC-adhesion properties that contribute to parasite sequestration and disease pathogenesisin vivo. The mechanism by which α+thalassemia on its own protects against severe malaria remains unresolved.