Table 2.
Red blood cell polymorphisms and mechanism of protection against severe malaria.
| Name | Gene affected | Polymorphisms | Mechanism of protection | References |
|---|---|---|---|---|
| Invasion | ||||
| Membrane proteins | ||||
| Duffy negative | FY | GATA-1 motif | Duffy-negative RBCs fail to form an apical junction and prevents invasion of P. vivax and P. knowlesi | [3] |
| Glycophorin C deficiency | GYP C | Exon3 deletion | Protection against EBA-140-mediated invasion by P. falciparum parasites. Mechanism in common with other causes of ovalocytosis | [48, 49] |
| Band 3 | SLC4A1 | 27 bp deletion | Resistance to invasion. Increased adhesion of P. falciparum-infected ovalocytes to CD36, thus reducing neurovascular binding of iRBCs in the brain | [48] |
| CR proteins | CR1 | Sl2 or McCb | Reduced ability of P. falciparum—infected CR1—deficient red blood cells to form rosettes | [50] |
| ABO | ABO GlycosylT | Polymorphisms in exon 6 and 7 | Loss of ABO Glycosyltransferase function results in the O blood group which prevents rosette formation | [51] |
| Replication within the RBC and/or elimination of iRBC | ||||
| RBC enzymes | ||||
| G6PD deficiency | G6PD | A376G/G202A [G6PD(A–)] | Early phagocytosis of iRBCs | [52] |
| PK deficiency | PKLR | *About 200 variants | Reduced rate of parasite replication within RBC and enhanced phagocytosis | [53] |
| Hemoglobinopathies | ||||
| (i) Structural variants | ||||
| HbS | HBB | β6: glutamate to valine | Increased sickling of parasitized erythrocytes leading to enhanced clearance by the spleen. Reduced erythrocyte invasion, early phagocytosis, and inhibited parasite growth under low oxygen tension in venous microvessels. Altered PfEMP-1 display and reduced cytoadherence of parasitized erythrocytes Enhancement of innate and acquired immunity | [1, 54] |
| HbC | HBB | β6: glutamate to lysine | Altered PfEMP-1 display and reduced cytoadherence of parasitized erythrocytes | [55] |
| HbE | HBB | β26: glutamate to lysine | Unidentified membrane abnormality renders resistant to invasion | [56] |
| (ii) Thalassemia | ||||
| α-thalassemia | HBA1/HBA2 | 3.7-kb deletion | Reduced expression of CR1 reduces P. falciparum resetting and confers protection against severe malaria. Increased microerythrocyte count in homozygotes reduces the amount of hemoglobin lost for any given parasite density, thus protecting against severe anemia | [1] |
*Population distribution of variants are yet to be established.