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 common 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.
Development of genetic resistance to malaria
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.
Mutations may have detrimental as well as beneficial effects, and any single mutation may have both. Infectiousness of malaria depends on specific proteins present in the cell walls and elsewhere in red blood cells. Protective mutations alter these proteins in ways that make them inaccessible to malaria organisms. However, these changes also alter the functioning and form of red blood cells that may have visible effects, either overtly, or by microscopic examination of red blood cells. These changes may impair the function of red blood cells in various ways that have a detrimental effect on the health or longevity of the individual. However, if the net effect of protection against malaria outweighs the other detrimental effects, the protective mutation will tend to be retained and propagated from generation to generation.
These alterations which protect against malarial infections but impair red blood cells are generally considered blood disorders since they tend to have overt and detrimental effects. Their protective function has only in recent times, been discovered and acknowledged. Some of these blood disorders are sickle-cell anemia, thalassaemia, glucose-6-phosphate dehydrogenase deficiency, ovalocytosis, elliptocytosis and loss of the Gerbich antigen and the Duffy antigen. These names refer to various proteins, enzymes, and the shape or function of red blood cells.
Innate resistance
The potent effect of genetically controlled innate resistance is reflected in the probability of survival of young children in areas where malaria is endemic. It is necessary to study innate immunity in the susceptible age group (younger than four years) because, in older children and adults, the effects of innate immunity are overshadowed by those of adaptive immunity. It is also necessary to study populations in which random use of antimalarial drugs does not occur. Some early contributions on innate resistance to infections of vertebrates, including humans, are summarized in Table 1. +Table 1. Innate Resistance to Plasmodia Year of discovery Pathogen Mechanism of resistance Authors 1954 P. falciparum Sickle-cell heterozygote Allison 1975 P. knowlesi Non-expression of Duffy antigen on red cells Miller, et al. 1976 P. vivax Non-expression of Duffy antigen on red cells Miller et al.
It is remarkable that two of the pioneering studies were on malaria. The classical studies on the Toll receptor in Drosophila fruit fly were rapidly extended to Toll-like receptors in mammals and then to other pattern recognition receptors, which play important roles in innate immunity. However, the early contributions on malaria remain as classical examples of innate resistance, which have stood the test of time.
Mechanisms of protection The mechanisms by which erythrocytes containing abnormal hemoglobins, or are G6PD deficient, are partially protected against P. falciparum infections are not fully understood, although there has been no shortage of suggestions. During the peripheral blood stage of replication malaria parasites have a high rate of oxygen consumption and ingest large amounts of hemoglobin. It is likely that HbS in endocytic vesicles is deoxygenated, polymerizes and is poorly digested. In red cells containing abnormal hemoglobins, or which are G6PD deficient, oxygen radicals are produced, and malaria parasites induce additional oxidative stress. This can result in changes in red cell membranes, including translocation of phosphatidylserine to their surface, followed by macrophage recognition and ingestion. The authors suggest that this mechanism is likely to occur earlier in abnormal than in normal red cells, thereby restricting multiplication in the former. In addition, binding of parasitized sickle cells to endothelial cells is significantly decreased because of an altered display of P. falciparum erythrocyte membrane protein-1 (PfMP-1). This protein is the parasite's main cytoadherence ligand and virulence factor on the cell surface. During the late stages of parasite replication red cells are adherent to venous endothelium, and inhibiting this attachment could suppress replication.
Sickle hemoglobin induces the expression of heme oxygenase-1 in hematopoietic cells. Carbon monoxide, a byproduct of heme catabolism by heme oxygenase-1(HO-1), prevents an accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of experimental cerebral malaria. Other mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have been described.
Types of innate resistance The first line of defense against malaria is mainly exerted by abnormal hemoglobins and glucose-6-phosphate dehydrogenase deficiency. The three major types of inherited genetic resistance – sickle cell disease, thalassemias, and G6PD deficiency – were present in the Mediterranean world by the time of the Roman Empire.
Hemoglobin abnormalities
Distribution of abnormal hemoglobins
Malaria does not occur in the cooler, drier climates of the highlands in the tropical and subtropical regions of the world. Tens of thousands of individuals have been studied, and high frequencies of abnormal hemoglobins have not been found in any population that was malaria-free. The frequencies of abnormal hemoglobins in different populations vary greatly, but some are undoubtedly polymorphic, having frequencies higher than expected by recurrent mutation. There is no longer doubt that malarial selection played a major role in the distribution of all these polymorphisms. All of these are in malarious areas, Sickle cell – The gene for HbS associated with sickle-cell is today distributed widely throughout sub-Saharan Africa, the Middle East, and parts of the Indian subcontinent, where carrier frequencies range from 5–40% or more of the population. Frequencies of sickle-cell heterozygotes were 20–40% in malarious areas of Kenya, Uganda, and Tanzania. Later studies by many investigators filled in the picture. High frequencies of the HbS gene are confined to a broad belt across Central Africa, but excluding most of Ethiopia and the East African highlands; this corresponds closely to areas of malaria transmission. Sickle-cell heterozygote frequencies up to 20% also occur in pockets of India and Greece that were formerly highly malarious.
The thalassemias have a high incidence in a broad band extending from the Mediterranean basin and parts of Africa, throughout the Middle East, the Indian subcontinent, Southeast Asia, Melanesia, and into the Pacific Islands. α-thalassemia, which attains frequencies of 30% in parts of West Africa; β-thalassemia, with frequencies up to 10% in parts of Italy; HbE, which attains frequencies up to 55% in Thailand and other Southeast Asian countries; HbE is found in the eastern half of the Indian subcontinent and throughout Southeast Asia, where, in some areas, carrier rates may exceed 60% of the population. HbC, which attains frequencies approaching 20% in northern Ghana and Burkina-Faso. HbC is restricted to parts of West and North Africa. concurrent polymorphisms – double heterozygotes for HbS and β-thalassemia, and for HbS and HbC, suffer from variant forms of sickle-cell disease, milder than SS but likely to reduce fitness before modern treatment was available. As predicted, these variant alleles tend to be mutually exclusive in populations. There is a negative correlation between frequencies of HbS and β-thalassemia in different parts of Greece and of HbS and HbC in West Africa. Where there is no adverse interaction of mutations, as in the case of abnormal hemoglobins and G6PD deficiency, a positive correlation of these variant alleles in populations would be expected and is found.
Sickle-cell