P falciparum malaria has modified the human genome considerably in endemic regions of the world. Most of the genes selected by malaria are hereditary red cell defects, as the sickle gene, the thalassemias, HbC, G-6PD deficiency, Southeast Asia ovalocytosis, and HbE. The last one might be the most frequent malaria-related genetic red cell defect in the world. In recent times, this mutation has appeared in nonendemic regions, including this country, by virtue of gene flow.
Chotivanich and colleagues (page 1172) describe an interesting finding: red cells of heterozygotes for HbE (AE) reduce the P falciparum invasion fourfold compared with AA cells and threefold compared with other red cell mutations, affording the host innate resistance. This finding places AE red cells in the same category as Southeast Asia ovalocytosis. In both, red cell membrane abnormalities appear to interfere with the complex dance involved in merozoite red cell invasion: lateral adherence, followed by apical adherence, then penetration, and finally release into the cytosol. AE red cell membrane defect could interfere with the process of invasion in one or several of these steps.
The paper also stimulates new questions. It is puzzling that HbE/β thalassemia (a severe disease) and homozygote EE red cells, a mild clinical condition, exhibit only a small invasion barrier. The case of HbE/β thalassemia is particularly puzzling, since β-thalassemia intermedia is known to damage the red cell cytoskeleton.
Moreover, the data in this paper and the previous findings by others of the partial inhibition of parasite growth in EE red cells suggest that EE and HbE/β thalassemia might represent an alternative, anti–P falciparum strategies yet to be elucidated. A new chapter seems to be unfolding in the genome's quest for providing the host, if not with protection against acquiring malaria, at least from dying of malaria.
