According to JBS Haldane, infectious diseases like malaria influence the frequency of genes that provide resistance. He introduced the concepts of “selective advantage of the heterozygote” and “balanced polymorphism” meaning that a mutant allele provides a selective advantage in the heterozygote but has lethal or severe outcome in the homozygote. Thus the frequency of heterozygotes increases until it is balanced by the negative effects of the homozygous state (Haldane’s malaria hypothesis). Two protective mutations are considered here. The first is sickle cell trait, where heterozygous carriers (HbAS, “sickle cell trait” carriers) are more effectively protected compared to every other red blood cell (RBC) mutation. The second is the deficiency of the RBC enzyme glucose-6-phosphate dehydrogenase (G6PD), widespread in some Italian regions previously heavily affected by malaria. Sickle cell trait was shown by several large case-control studies to be 90% protective against cerebral malaria and severe anemia, the most frequent causes of death. G6PD-deficiency provides 46-58% protection against severe and mild malaria in female heterozygotes and male hemizygotes. The predominant explanation of resistance is that the mutant RBCs do not sustain parasite invasion, or intracellular parasite development. Several supportive in vitro studies often failed to reproduce the very complex situation found in vivo, and/or made use of inadequate culture media. Recent studies have shown no difference in invasion and parasite growth in parasites developing in normal compared to HbAS or G6PD-deficient RBCs. We propose here an alternative explanation based on enhanced phagocytosis of early parasite forms (ring forms) when the parasites are developing in mutant RBCs. The molecular nature of HbAS and G6PD-deficiency is different. However, mutant RBCs produce increased amounts of reactive oxygen species (ROS), due to the intrinsic characteristics of the mutant HbS hemoglobin or the defective anti-oxidant defense in G6PD deficiency. We have recently shown that the parasite developing in mutant RBCs enhanced the baseline oxidative changes in the host RBC, and specifically induced selective ring phagocytosis. The differences in phagocytosis of mutant- vs non-mutant parasitized RBCs were ring-specific and vanished at trophozoite stage. We suggest that enhanced and preferential phagocytosis of ring-parasitized RBCs may be advantageous to the host because it reduces parasite growth and parasite density, and lowers the number of late-stage parasites adherent to venular endothelia. Adhesion of trophozoites and schizonts to endothelia in several important organs (lungs, kidneys, brain, bone marrow and placenta) appears indeed to be responsible for severe forms of malaria, such as cerebral malaria, placental malaria, possibly malarial dyserythropoiesis and respiratory distress.
How genetics and biology helped humanity to survive falciparum malaria
ARESE, Paolo
2006-01-01
Abstract
According to JBS Haldane, infectious diseases like malaria influence the frequency of genes that provide resistance. He introduced the concepts of “selective advantage of the heterozygote” and “balanced polymorphism” meaning that a mutant allele provides a selective advantage in the heterozygote but has lethal or severe outcome in the homozygote. Thus the frequency of heterozygotes increases until it is balanced by the negative effects of the homozygous state (Haldane’s malaria hypothesis). Two protective mutations are considered here. The first is sickle cell trait, where heterozygous carriers (HbAS, “sickle cell trait” carriers) are more effectively protected compared to every other red blood cell (RBC) mutation. The second is the deficiency of the RBC enzyme glucose-6-phosphate dehydrogenase (G6PD), widespread in some Italian regions previously heavily affected by malaria. Sickle cell trait was shown by several large case-control studies to be 90% protective against cerebral malaria and severe anemia, the most frequent causes of death. G6PD-deficiency provides 46-58% protection against severe and mild malaria in female heterozygotes and male hemizygotes. The predominant explanation of resistance is that the mutant RBCs do not sustain parasite invasion, or intracellular parasite development. Several supportive in vitro studies often failed to reproduce the very complex situation found in vivo, and/or made use of inadequate culture media. Recent studies have shown no difference in invasion and parasite growth in parasites developing in normal compared to HbAS or G6PD-deficient RBCs. We propose here an alternative explanation based on enhanced phagocytosis of early parasite forms (ring forms) when the parasites are developing in mutant RBCs. The molecular nature of HbAS and G6PD-deficiency is different. However, mutant RBCs produce increased amounts of reactive oxygen species (ROS), due to the intrinsic characteristics of the mutant HbS hemoglobin or the defective anti-oxidant defense in G6PD deficiency. We have recently shown that the parasite developing in mutant RBCs enhanced the baseline oxidative changes in the host RBC, and specifically induced selective ring phagocytosis. The differences in phagocytosis of mutant- vs non-mutant parasitized RBCs were ring-specific and vanished at trophozoite stage. We suggest that enhanced and preferential phagocytosis of ring-parasitized RBCs may be advantageous to the host because it reduces parasite growth and parasite density, and lowers the number of late-stage parasites adherent to venular endothelia. Adhesion of trophozoites and schizonts to endothelia in several important organs (lungs, kidneys, brain, bone marrow and placenta) appears indeed to be responsible for severe forms of malaria, such as cerebral malaria, placental malaria, possibly malarial dyserythropoiesis and respiratory distress.
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