Resistance to Malaria
A number of genetic factors provide some resistance to infection by various Plasmodium spp. Hemoglobin S, thalassemia, and glucose-6-phosphate dehydrogenase or G6PD deficiency are associated with increased resistance to Plasmodium falciparum.
- People with G6PD deficiency are protected against the severe effects of falciparum malaria.
- Individuals with sickle cell trait (heterozygotes) are protected against malaria because their red blood cells have too little ATPase activity and can not produce sufficient energy to support the growth of the parasite. People with homozygous sickle cell anemia are also protected but rarely live long enough to obtain much benefits.
- Apparently, the Duffy negative RBCs convey increased resistance to infection with Plasmodium vivax. The receptor for P. vivax is the Duffy blood group antigen. More than 90% of black west Africans and many of their American descendants do not produce the Duffy antigen and are thereby resistant to vivax malaria.
Sickle Cell Anemia and Malaria
In my undergraduate teaching class, one of the most common queries of students is; “Are people with sickle cell anemia protected against malaria“?
The above query is only partially right because:
- Sickle cell hemoglobin confers a survival advantage against malaria. However, there is no clear-cut understanding/postulates about how sickle cell anemia confers immunity against malaria.
- People with sickle cell anemia do suffer from malaria, and very badly too. Malaria is the commonest cause of the sickle cell crisis in Africa.
To understand the relationship between sickle cell anemia and malaria, one must have knowledge about sickle cell anemia, life cycle of malarial parasite, and how the sickle cell shape of RBC may affect the life cycle of the malarial parasite.
Sickle Cell Anemia
It is a serious blood disorder in which the body makes sickle-shaped (crescent-shaped) red blood cells (RBC). Normal RBCs are disc-shaped and look like doughnuts without holes in the center. They move easily through blood vessels. Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. Sickle hemoglobin causes the cells to develop a sickle, or crescent, shape.
Sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs. Blocked blood flow can cause pain and organ damage. It can also raise the risk of infection.
As far as adult hemoglobin types are concerned when dealing with malaria, there are 3 broad phenotypes in adults
- ‘AA’: Normal population
- ‘SS’: Sickle-cell anemia
- Sickle cell trait (genotype HbAS)
Only those individuals that inherit two copies of the sickle mutation (one from their mother and the other from their father) develop sickle cell anemia. If untreated, these individuals have a shorter than normal life expectancy.
Life Cycle of Malaria and effect of Sickle cell trait
When a female Anopheline mosquito bites a person and injects malarial parasites into the body, the malarial parasite (Plasmodium falciparum) first completes one cycle of pre-erythrocytic schizogony in liver cells. Then it invades the RBCs and multiplies within them until they burst, releasing more parasites (merozoites) into the body, to produce severe febrile illness with serious consequences.
In the sickle cell trait (AS), however, as soon as the malarial parasite Plasmodium falciparum begins to multiply in the RBCs, using up the cell’s oxygen supply, the AS cell changes from round to sickle shape. Reduced oxygen levels result in diminished parasite growth. Apart from this, the malarial parasite cannot complete its life cycle due to cell sickling and destruction in RBCs (erythrocytic schizogony) preventing further progress of the disease.
Sickle Cell Trait and Resistance with Malaria
Malaria resistance by the sickle cell trait still remains the subject of considerable debate. Sickle cell trait (genotype HbAS) confers a high degree of resistance to severe and complicated malaria yet the precise mechanism remains unknown.
Individuals carrying just one copy of the sickle mutation- sickle cell trait (inherited from either father or mother) do not develop sickle cell anemia and lead normal lives. However, it was found that these same individuals were in fact highly protected against malaria, thus explaining the high prevalence of this mutation in geographical areas where malaria is endemic.
Postulated Hypothesis (Research) for Resistance
- Reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes
- Parasite-infected HbAS RBCs tend to sickle, a process that may result in their premature destruction by the spleen
- HbAS involves the enhancement of not only innate but also acquired immunity to the parasite.
- Sickle cell hemoglobin confers a survival advantage against malaria by inducing the production of heme oxygenase-1 (HO-1) without affecting the normal infection cycle of malaria in RBCs.
In-person suffering from sickle cell anemia (homozygous SS hemoglobin gene) the effects of fever, diarrhea, and vomiting provoked a sickle crisis that cannot outweigh any beneficial effect of sickling-against-malarial-parasite.
To be a sickle cell trait (AS) in a malarious environment appears to be better than not having sickle genes at all (AA), or having 2 sickle genes (SS).
Watch interactive Video: “Relation between Malaria and Sickle Cell Anemia“