Lethal diseases that save lives: Sickle Cell Anemia and Malarial resistance

As a go-to example for a classic genetic disorder, sickle cell anemia has been used in many a college biology course. It is a recessive autosomal disease due to a base pair substitution mutation in the ß-globin gene of hemoglobin that, when present, causes red blood cells to become shriveled and shaped like the farm tool for which the illness was named.  Individuals with both alleles for sickle cell suffer through a painful daily struggle with normal blood circulation and rarely mature to a reproductive age. So why has this disease persisted through the years? Despite the terrible consequences that accompany a homozygous sickle genotype, evolution may have provided an answer. Malaria has long been known for the damage that it causes to the human populous in tropical regions. Which conveniently, is where sickle cell disease is typically seen the most. Malarial transmission through mosquitos from one host to another can be fatal. In 2010, there was an estimated 863,000 deaths globally due to malaria (Hedrick, 2012). The heterozygous individuals with a single sickle cell allele and a normal adult hemoglobin allele interestingly show a partial phenotype of sickle cell anemia that is accompanied with a resistance to severe malaria. 

The HbS allele has been hypothesized to correlate with symptomatic variants of malaria. The presence of the HbS allele has shown a resistance to symptomatic malaria, but not asymptomatic (Shim, 2013). This means that the HbS allele does not prevent infection of the host but the manifestation of the parasite into full-blown malaria. Three plausible mechanisms for prevention of parasite maturation have been suggested by modern research: 

1. Once a red blood cell is infected, the parasite forces the cell into a state of rapid oxygen consumption as it mines its host’s actin to transport proteins to the red blood cell surface. This causes a decrease in the cell’s partial pressure of oxygen, which could induce the sickling of the red blood cell marking it for macrophage uptake (Taylor, 2013).  

2. When a sickled cell is infected, parasitic knob proteins like PFEMP1 typically used to adhere to epithelial tissue are prevented by the deformed hemoglobin aggregates from being transported to the outer membrane of the infected cell.  Preventing further propagation of the disease through the body. Figure 1 illustrates suggested mechanisms 1 and 2 (Bunn, 2013).

 3. Host integration of microRNAs (miRNA) into the parasitic mRNA inhibits parasitic protein translation via the creation of chimeric mRNA. Transfection of these miRNAs into infected HbAA cells showed a roughly 50% decrease in parasite proliferation. Upon closer examination, it was seen that this effect was caused by the integration of the miRNA into host mRNA. Figure 2 represents the third suggested mechanism (Bunn, 2013). 

Although the exact mechanism for sickle cell's contribution to malarial resistance has not been determined, it provides us with an opportunity to learn more from the disease. Nature has provided its own imperfect antidote to malaria. Perhaps if we can figure out how sickled cells prevent symptomatic malaria we may be able to develop a drug using a similar approach.

Figure 1: Mechanisms underlying protection by AS RBS against falciparum malaria

Figure 2: Inhibition of translation of parasite mRNAs by micro RNAs in AS RBCs

References:

Bunn, H. F. (2013). The triumph of good over evil: Protection by the sickle gene against malaria. Blood, 121(1), 20-25.

Hedrick, P. W. (2012). Resistance to malaria in humans: The impact of strong, recent selection. Malaria Journal, 11, 349.

Taylor, S. M., Cerami, C., & Fairhurst, R. M. (2013). Hemoglobinopathies: Slicing the gordian knot of plasmodium falciparum malaria pathogenesis. Plos Pathogens, 9(5), e1003327.