Inborn Immunity to Malaria: Sickle-Cell Anemia

Nature has devised a fascinating defense against malaria. It involves altering the very shape of the body's red blood cells (RBC). Sickle cell anemia is a disorder that changes the shape of RBC, as shown in the picture below, due to a mutation in the genetic code that is responsible for the formation of the beta-subunit portion of a hemoglobin molecule. As a result, the RBC will take a rigid sickled-shape. This leads to two important consequences: 1) malaria immunity and 2) organ damage and anemia symptoms.

Normal RBC compared with a sickle shaped one.

A mutation in the genetic code for hemoglobin causes sickle-cell anemia.
The mutation codes for a valine rather than a glutamic acid to be produced.

How do does sickle cell anemia make a person immune to malaria? The parasite is actually incapable of infecting the red blood cells. The RBC shape is inhospitable. A certain enzyme (oxygenase-1 (HO-1)) is activated strongly by the presence of sickle hemoglobin which produces carbon monoxide, which lends another line of defense against the parasite. People in regions of the world with high rates of malaria show a high frequency of sickle cell genes. This has provided a natural protection against the disease, and leads to natural selection for the genes because individuals have a survival advantage over those who do not.

Red blood cells (RBC) that are functional are round and flexible, and therefore travel easily through blood vessels of all sized. The stiff, sickled shape prevents normal movement and the cells pile up on top of one another, creating a clot and blockage of the blood vessel. This is dangerous, and can be extremely painful. Sickle cell anemia makes the RBC less functional, preventing them from transporting sufficient oxygen to the organs and muscles. Sickled RBC also die before healthy RBC, which leads to lower blood count and therefore anemia. and cannot travel properly through blood vessels. They are also incapable of transporting oxygen and iron efficiently throughout the body.

The disorder affects the autosomes (chromosomes that aren't the X or Y chromosomes). Humans have 23 pairs of chromosomes, the first 22 being autosomes and the final pair being sex chromosomes. This final pair determines your gender: females are XX and males XY. Sickle cell anemia is an autosomal recessive disorder, caused by a mutation on the 11th chromosome. This means that both of the person's chromosomes in a pair must carry the mutation in DNA. So both parents must carry pass the defective gene onto the offspring for sickle cell anemia to occur.

 

Depiction of normal and sickle cell hemoglobin and the red blood cells corresponding to each.
From University of Utah Health Sciences Learn. Genetics

There is a strong connection between sickle cell frequency and malaria in Africa

The highest rates of sickle cell anemia are seen in Africa and India. Parts of the
Mediterranean are still affected as well.