Mechanisms by Which Sickle Cell Protects Against Malaria
Mechanisms by Which Sickle Cell Protects Against Malaria
It is likely that both biochemical and immune mechanisms contribute to the protection afforded against falciparum malaria by the HbAS genotype. HbS clearly induces biochemical changes in the red blood cell that may affect parasite metabolism and growth. Plasmodium falciparum also likely inflicts oxidative damage on the HbAS red blood cell. Chronic low levels of oxidized haem in sickled red blood cells may induce HO-1, leading to host tolerance in severe disease. Oxidized haem may also interfere with the formation of an actin cytoskeleton, leading to altered PfEMP-1 expression on the infected red blood cell surface membrane and reduced cytoadherence. Reduced cytoadherence may lead to decreased endothelial activation and decreased inflammation implicated in the pathogenesis of severe malaria. In addition, it could also lead to increased splenic uptake of infected erythrocytes. Within the spleen, increased antigen presentation may lead to accelerated development of protective immune responses, including antibodies to PfEMP-1, potentially augmented by biochemical protection against high parasite densities that might otherwise dampen an effective response. Higher levels of antibodies directed against PfEMP-1 and possibly other surface proteins may enhance opsonization and phagocytosis of infected red blood cells and further destabilize the cytoadherence properties of infected red blood cells. While there are some data to support all of these mechanisms, it is still unclear which ones are relevant in vivo. Together, however, it is clear that relevant mechanisms lead to better control of parasitaemia in HbAS children and protect against both uncomplicated and severe malaria. Improved understanding of the mechanisms of protection derived from this single point mutation will give further insight into the host-parasite relationship including how P. falciparum interacts with the human immune system.
Conclusions
It is likely that both biochemical and immune mechanisms contribute to the protection afforded against falciparum malaria by the HbAS genotype. HbS clearly induces biochemical changes in the red blood cell that may affect parasite metabolism and growth. Plasmodium falciparum also likely inflicts oxidative damage on the HbAS red blood cell. Chronic low levels of oxidized haem in sickled red blood cells may induce HO-1, leading to host tolerance in severe disease. Oxidized haem may also interfere with the formation of an actin cytoskeleton, leading to altered PfEMP-1 expression on the infected red blood cell surface membrane and reduced cytoadherence. Reduced cytoadherence may lead to decreased endothelial activation and decreased inflammation implicated in the pathogenesis of severe malaria. In addition, it could also lead to increased splenic uptake of infected erythrocytes. Within the spleen, increased antigen presentation may lead to accelerated development of protective immune responses, including antibodies to PfEMP-1, potentially augmented by biochemical protection against high parasite densities that might otherwise dampen an effective response. Higher levels of antibodies directed against PfEMP-1 and possibly other surface proteins may enhance opsonization and phagocytosis of infected red blood cells and further destabilize the cytoadherence properties of infected red blood cells. While there are some data to support all of these mechanisms, it is still unclear which ones are relevant in vivo. Together, however, it is clear that relevant mechanisms lead to better control of parasitaemia in HbAS children and protect against both uncomplicated and severe malaria. Improved understanding of the mechanisms of protection derived from this single point mutation will give further insight into the host-parasite relationship including how P. falciparum interacts with the human immune system.
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