Abstract
BackgroundSickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia. Although several candidate mechanisms have been proposed, their epidemiological, clinical and experimental correlates have not been adequately explained. To explore the basis for generally lower parasitaemias and delayed malaria episodes in children with HbAS, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in children with normal haemoglobin A (HbAA).MethodsThe mechanical splenic retention of Plasmodium falciparum-infected RBCs from subjects with HbAS or HbAA was investigated using two physiologically relevant methods: microsphiltration and ex vivo spleen perfusion. P. falciparum-infected RBCs obtained from in vitro cultures and from patients were used in either normoxic or hypoxic conditions. The effect of sickling in ring-infected HbAS RBCs was also investigated.ResultsWhen a laboratory-adapted parasite strain was analysed, ring-infected HbAA RBCs were retained in microsphilters at similar or greater levels than ring-infected HbAS RBCs, under normoxic (retention rate 62.5 vs 43.8 %, P < 0.01) and hypoxic (54.0 vs 38.0 %, P = 0.11) conditions. When parasitized RBCs from Malian children were analysed, retention of ring-infected HbAA and HbAS RBCs was similar when tested either directly ex vivo (32.1 vs 28.7 %, P = 0.52) or after one re-invasion in vitro (55.9 vs 43.7 %, P = 0.30). In hypoxia, sickling of uninfected and ring-infected HbAS RBCs (8.6 vs 5.7 %, P = 0.51), and retention of ring-infected HbAA and HbAS RBCs in microsphilters (72.5 vs 68.8 %, P = 0.38) and spleens (41.2 vs 30.4 %, P = 0.11), also did not differ. Retention of HbAS and HbAA RBCs infected with mature P. falciparum stages was greater than 95 %.ConclusionsSickle-cell trait is not associated with higher retention or sickling of ring-infected RBCs in experimental systems reflecting the mechanical sensing of RBCs by the human spleen. As observed with HbAA RBCs, HbAS RBCs infected with mature parasites are completely retained. Because the cytoadherence of HbAS RBCs infected with mature parasites is impaired, the very efficient splenic retention of such non-adherent infected RBCs is expected to result in a slower rise of P. falciparum parasitaemia in sickle-cell trait carriers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1522-0) contains supplementary material, which is available to authorized users.
Highlights
Sickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia
Diakité et al Malar J (2016) 15:482 mature parasites is impaired, the very efficient splenic retention of such non-adherent infected red blood cells (RBCs) is expected to result in a slower rise of P. falciparum parasitaemia in sickle-cell trait carriers
Retention of Plasmodium falciparum ring‐infected HbAA and HbAS RBCs To mimic the situation occurring in human subjects, the relative retention rates of infected HbAA RBCs vs all HbAA RBCs, or HbAS RBCs vs all HbAS RBCs, were determined
Summary
Sickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia. To explore the basis for generally lower parasitaemias and delayed malaria episodes in children with HbAS, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in children with normal haemoglobin A (HbAA). To explore the basis for generally lower parasitaemias and delayed malaria episodes in HbAS children, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in HbAA children. Such an effect would achieve a lower parasitaemia that would be tolerated without symptoms, and delay progression to a higher parasitaemia that produces symptoms [13, 14]. While several studies have reported no differences between HbAS and HbAA children in the intensity of adaptive immune responses to parasite antigens [16,17,18], others have reported some differences [19]
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