Sickle cell trait provides a survival advantage over people with normal hemoglobin in regions where malaria is endemic. The trait is known to cause significantly fewer deaths due to malaria, especially when plasmodium falciparum is the causative organism. This is a prime example of natural selection
, SS evident by the fact that the geographical distribution of the gene (for hemoglobin S) and the distribution of malaria in Africa virtually overlap. Because of the unique survival advantage, people with the trait increase in number as more people infected with malaria and having the normal hemoglobin tend to succumb to the complications. (Shear, et al, 1993).
Although the precise mechanism for this phenomenon is not known, a several factors are believed to be responsible.
- Infected erythrocytes (Red Blood cells) tend to have lower oxygen tension, because it is significantly reduced by the parasite. This causes sickling of that particular erythrocyte.
- Signaling the phagocytes to get rid of the cell and hence the parasite within.
- Since the sickling of parasite infected cells is higher, these selectively get removed by the reticulo-endothelial system, thus sparing the normal erythrocytes.
- Excessive vacuole formation occurs in those parasites infecting sickle cells.
- Sickle trait erythrocytes produce higher levels of the superoxide anion and hydrogen complicated malaria, peroxide than do normal erythrocytes, both are toxic to malarial parasites (Friedman, 1978). The sickle cell trait was found to be 50% protective against mild clinical malaria, 75% protective.
MECHANISMS OF PROTECTION
The mechanisms of which erythrocytes containing abnormal hemoglobins, or are G6PD deficient, are partially protected against P. falciparum infections are not fully understood, although there has been no shortage of suggestions. During the peripheral blood stage of replication malaria parasites have a high rate of oxygen consumption (Vaidya and Mather 2009) and ingest large amounts of hemoglobin. (Elliott, et al 2008). It is likely that HbS in endocytic vesicles is deoxygenated, polymerizes and is poorly digested.
In red cells containing abnormal hemoglobins, or which are G6PD deficient, oxygen radicals are produced, and malaria parasites induce additional oxidative stress. This can result in changes in red cell membranes, including translocation of phosphatidylserine to their surface, followed by macrophage recognition and ingestion. (Foller, et al 2009). The authors suggest that this mechanism is likely to occur earlier in abnormal than in normal red cells, thereby restricting multiplication in the former.
In addition, binding of parasitized sickle cells to endothelial cells is significantly decreased because of an altered display of P. falciparum erythrocyte membrane protein-1 (PfMP-1). (Cholera, et al, 2008). This protein is the parasite’s main cytoadherence ligand and virulence factor on the cell surface. During the late stages of parasite replication red cells are adherent to venous endothelium, and inhibiting this attachment could suppress replication.