Sickle cell trait occur when someone inherits a normal hemoglobin gene from one parent (HbA) and a sickle hemoglobin gene (HbS) from the other (resulting in HbAS).
People (particularly children) infected with P. falciparum are more likely to survive the acute illness if they have sickle cell trait. The precise mechanism by which sickle cell trait imparts resistance to malaria is unknown.
A number of factors are likely to be involved and contribute in varying degrees to the defense against malaria. Several theories were proposed to explain why people with sickle cell trait have milder cases of malaria. Some are
I. The parasite inside the red cell produces acid. In the presence of acid, HbS has a tendency to polymerize which causes the cells to sickle. Since sickled cells are destroyed as the blood circulates through the spleen, the parasites are destroyed as well.
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II. Deformation of sickle trait erythrocytes would mark these cells as abnormal and target them for destruction by phagocytes. Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells
III. Oxygen radical formation in sickle trait erythrocytes retards growth and even kills the P. falciparum parasite
IV. Malarial parasites do not live long under low oxygen conditions. Since the oxygen concentration is low in the spleen, and since infected red cells tend to get trapped in the spleen, they may be killed there.
V, Another thing that happens under low oxygen conditions is that potassium leaks out of HbS-containing cells. The parasite needs high potassium levels to develop. This may be the reason why the parasite fails to thrive in red blood containing Hb S.
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Hemoglobin C and malaria: Hemoglobin C heterozygotes had significantly fewer episodes of P. falciparum malaria when compared with only hemoglobin A.
The risk of malaria was still lower in subjects who were homozygous for hemoglobin C. Homozygous hemoglobin C produces a mild hemolytic anemia and splenomegaly.
The much milder phenotype of the condition relative to homozygous hemoglobin S led the investigators to speculate that without medical intervention for malaria; hemoglobin C would replace hemoglobin S over the next few thousand years as the dominant “antimalarial”.