Only the erythrocytic form of malaria is associated with disease, so valuable information about which African children are likely to have more, or less, severe malaria has inevitably been obtained from examining the inborn RBC abnormalities that endemic malaria has selected across the tropics.
The coinciding geographic distributions of malaria transmission and the thalassaemias prompted Haldane to put forward the 'malaria hypothesis', which proposed that common erythrocyte abnormalities are selected because of the fitness advantage they confer against malaria . Sickle cell haemoglobin (HbS) has also been repeatedly shown to be associated with malaria resistance, with heterozygotes for the HbS trait demonstrating 10% of the population at risk for severe malaria in certain populations . Other haemoglobinopathies (e.g. HbC [179, 180] and HbE ) and deficiencies in RBC enzymes (e.g. glucose-6-phosphate dehydrogenase deficiency ) have also been linked with protection against severe malaria. The mechanisms of protection afforded by haemoglobinopathies are likely to be multi-factorial. Studies have demonstrated evidence to support several independent mechanisms including: reduced parasite invasion of RBCs and diminished intraerythrocytic growth of parasites in patients with the HbS trait , enhanced phagocytosis of parasite-infected erythrocytes (IEs)  and enhanced immune responses against IEs .
Recent in vitro studies observed that HbC modifies the quantity and distribution of the variant antigen P. falciparum erythrocyte membrane protein 1(PfEMP1) on the IE surface. PfEMP1 has been implicated in numerous IE adhesive interactions. In the latter study the authors demonstrated that HbC reduces the level of IE adhesion to endothelial monolayers, in addition to IE rosetting (the adhesion of IEs to uninfected erythrocytes) and IE agglutination by sera. These findings provide the prospect that HbC pro tects against severe malaria by mitigating the obstruction and inflammation caused by the PfEMP1-mediated adherence of IEs . However, sequestration is believed to enhance parasite survival by enabling IEs to avoid splenic clearance, so any reduction of sequestration by HbC can be expected to limit parasite fitness. Multiple epidemiology studies (e.g. [179, 187, 188]) have failed to identify any significant impact of HbC on the frequency or density of parasitaemia in naturally exposed populations. Consequently, the influence of the changes in IE surface conformation needs to be confirmed and further examined in vivo .
A recent study re-confirmed that African children with a-thalassaemia trait are significantly less likely to be hospitalised with severe malaria, particularly with coma or severe anaemia (Hb < 5 g/100 ml). It is intriguing that the a-thalassaemia patients did not demonstrate a lower incidence of uncomplicated malaria nor any reduction in peripheral parasite density . Thalassaemia has also been associated with increased incidence of clinical vivax and falciparum malaria during early life . The findings raise speculation that the trait may indirectly afford enhanced immunity through increased non-lethal exposure to malarial parasites. Such a mechanism is appealing, since it would be equally plausible across a range of hae-moglobinopathies, including HbC.
Variations in erythrocyte membrane proteins also have a profound influence on malaria susceptibility. Most notably the absence of Duffy antigen protein confers absolute protection to P. vivax infection. More recently, the Duffy antigen has also been associated with a protection against falciparum malaria .
Enzymes involved with iron handling may also have a critical influence on malaria morbidity. A recent study from the Gambia demonstrated that children in an endemic malaria area possessing the haptoglobin 2,2, isotype had a significantly increased risk of anaemia . However, a lack of parallel alterations in other haematinic indices leaves the mechanism of this process unclear.
Malarial protection within individuals exhibiting multiple RBC abnormalities appears even more complex. A recent study observed that the concurrent presence of sickle cell and a-thalassaemia trait among African children had a negative influence on the risk of malaria infection . The results warn geneticists that gene epistasis may have a profound influence on overall malarial susceptibility.
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