Sickle Cell Anaemia and Malaria — relationship status “ It’s complicated.”
On one hand, heterozygous carriers of the sickle cell gene are relatively protected while the homozygous patients are highly susceptible to the lethal forms of malaria.
Sickle cell disease is an inherited chronic hematological disorder, where a point mutation in the β globin gene resulting in the substitution of glutamic acid with valine at position 6 of the peptide. Red blood cells in sickle cell anemia die more quickly than their normal counterparts.
Humans, like most animals, are diploids which means we have paired chromosomes from each parent, hence two copies of each of our genes. Each copy of a gene is called an allele. Geneticists usually term the traits carried on in these genes as ‘dominant’ or ‘recessive’ based on their ability to express themselves in the next generation. As the name suggests, the dominant trait always overrides the recessive one. In case a person inherits a dominant and another recessive gene for the same trait, he/she will display the trait carried by the dominant allele. The recessive traits can express themselves only when present in the homozygous state i.e. when both the alleles carry the recessive trait.
The sickle cell anemia trait is found in the recessive allele of the hemoglobin gene. This means that you must have two copies of the recessive allele — one from your mother and another from your father to have the condition. It is a genetic condition that has an autosomal recessive inheritance pattern. But what about those with only one copy? These people are known as carriers. They are said to have sickle cell trait, but not sickle cell anemia (SCA). People with sickle cell trait carry only one copy of the altered hemoglobin gene and rarely have any clinical symptoms related to the disease. SCA is a disease of homozygotes (HbSS) — which is why we call it recessive - whereas heterozygotes (HbAS) are normal for most intents and purposes.
It is believed that in the current prevalence of malaria in endemic areas the carriers will have an advantage of being, in first approximation, ‘ malaria resistant’. But this resistant form should more likely to be considered as ‘relatively protected from dying of lethal forms of malaria’. Because the AS do get malaria but they tend to have a lower number of parasitized cells in their blood. Hence the infection tends to be less severe. Also, they are less likely to suffer from the two of the most fatal forms of malaria — cerebral malaria and malaria with severe anemia.
Finding the footprint
One of the proposed explanations for this kind of selective protection of Sickle cell trait from Plasmodium falciparum malaria is the plausible mechanism: namely that in AS heterozygotes P falciparum-infected red sickle cells and are then removed by macrophages. Various studies including clinical epidemiology are consistent with the theory that AS heterozygotes have better genetic makeup to survive in malaria overblown environment although there would be no advantage in an environment without malaria.
E A Beet first established that in the blood cells of an AS heterozygote with malaria: the red cell, which appears normal at the time of invasion, once infected undergoes sickling ( probably as a result of lowering of pH and deoxygenation caused by the parasite), and thus it falls an easy prey to the macrophages in the spleen and other organs. This was subsequently proved by various quantitative in vitro studies.
Interestingly though, malaria has been incriminated as a great cause of mortality in people with sickle cell disease (SCD) or the HbSS category. As sickle cell trait (SCT) offers relative protection against malaria, one might expect the protection to be at least as effective in the homozygous state.
The SCD population has a lower mortality rate related to malaria than the non-SCD population. Meanwhile, within the SCD population, those admitted with malaria are twice likely to die than those admitted for other pathologies. The downcast of malaria in SCD patients is that it not only worsens the pre-existing anemia in them, to the point of life-threatening but also hampers the splenic function hindering the clearance of parasitized RBCs. In Africa, malaria contributes substantially to the early mortality in patients with SCD.
Beet’s theory along with various in vitro culture studies have noticed normal growth of P falciparum in AS red blood cells as well as SS red cells, clearly indicating that it is not Hb S per se that hinders parasite propagation. If AS heterozygotes were protected from malaria through the failure of infection, one might expect it to be as effective in SS homozygotes. However, the mechanism is not the failure of infection.
It is widely stated that the protection of AS heterozygotes against malaria is not clear, over the last 50 years there has not been any evidence contradicting the sickling-phagocytosis model, and the elimination of parasite by phagocytosis of infected AS red cell has been confirmed.
