Genetic resistance to malaria

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most commonly alterations to molecules essential for red blood cell function (and therefore parasite survival), such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell. Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most commonly alterations to molecules essential for red blood cell function (and therefore parasite survival), such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell. These inherited changes to hemoglobin or other characteristic proteins, which are critical and rather invariant features of mammalian biochemistry, usually cause some kind of inherited disease. Therefore, they are commonly referred to by the names of the blood disorders associated with them, including sickle-cell disease, thalassemia, glucose-6-phosphate dehydrogenase deficiency, and others. These blood disorders cause increased morbidity and mortality in areas of the world where malaria is less prevalent. Microscopic parasites, like viruses, protozoans that cause malaria, and others, cannot replicate on their own and rely on a host to continue their life cycles. They replicate by invading the hosts' cells and usurping the cellular machinery to replicate themselves. Eventually, unchecked replication causes the cells to burst, killing the cells and releasing the infectious organisms into the bloodstream where they can infect other cells. As cells die and toxic products of invasive organism replication accumulate, disease symptoms appear. Because this process involves specific proteins produced by the infectious organism as well as the host cell, even a very small change in a critical protein may render infection difficult or impossible. Such changes might arise by a process of mutation in the gene that codes for the protein. If the change is in the gamete, that is, the sperm or egg that join to form a zygote that grows into a human being, the protective mutation will be inherited. Since lethal diseases kill many persons who lack protective mutations, in time, many persons in regions where lethal diseases are endemic come to inherit protective mutations. When the P. falciparum parasite infects a host cell, it alters the characteristics of the red blood cell membrane, making it 'stickier' to other cells. Clusters of parasitized red blood cells can exceed the size of the capillary circulation, adhere to the endothelium, and block circulation. When these blockages form in the blood vessels surrounding the brain, they cause cerebral hypoxia, resulting in neurological symptoms known as cerebral malaria. This condition is characterized by confusion, disorientation, and often terminal coma. It accounts for 80% of malaria deaths. Therefore, mutations that protect against malaria infection and lethality pose a significant advantage. Malaria has placed the strongest known selective pressure on the human genome since the origin of agriculture within the past 10,000 years. Plasmodium falciparum was probably not able to gain a foothold among African populations until larger sedentary communities emerged in association with the evolution of domestic agriculture in Africa (the agricultural revolution). Several inherited variants in red blood cells have become common in parts of the world where malaria is frequent as a result of selection exerted by this parasite. This selection was historically important as the first documented example of disease as an agent of natural selection in humans. It was also the first example of genetically controlled innate immunity that operates early in the course of infections, preceding adaptive immunity which exerts effects after several days. In malaria, as in other diseases, innate immunity leads into, and stimulates, adaptive immunity.