Human genetic resistance to malaria
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.
[citation needed] The potent effect of genetically controlled innate resistance is reflected in the probability of survival of young children in areas where malaria is endemic.
[citation needed] 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[8] and ingest large amounts of hemoglobin.
In red cells containing abnormal hemoglobins, or which are G6PD deficient, oxygen radicals are produced, and malaria parasites induce additional oxidative stress.
[10] This can result in changes in red cell membranes, including translocation of phosphatidylserine to their surface[jargon], followed by macrophage recognition and ingestion.
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.
All of these are in malarious areas,[citation needed] 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.
[20] The molecular basis of sickle cell anemia was finally elucidated in 1959 when Ingram perfected the techniques of tryptic peptide fingerprinting.
[25] Targeting the stimuli that lead to endothelial activation will constitute a promising therapeutic strategy to inhibit sickle red cell adhesion and vaso-occlusion.
[28] It has long been known that a kind of anemia, termed thalassemia, has a high frequency in some Mediterranean populations, including Greeks and southern Italians.
Vernon Ingram deserves the credit for explaining the genetic basis of different forms of thalassemia as an imbalance in the synthesis of the two polypeptide chains of hemoglobin.
[citation needed] The lower Himalayan foothills and Inner Terai or Doon Valleys of Nepal and India are highly malarial due to a warm climate and marshes sustained during the dry season by groundwater percolating down from the higher hills.
Medical studies among the Tharu and non-Tharu population of the Terai yielded the evidence that the prevalence of cases of residual malaria is nearly seven times lower among Tharus.
In a large case–control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC was associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes and of 93% in HbCC homozygotes.
HbE erythrocytes have an unidentified membrane abnormality that renders the majority of the RBC population relatively resistant to invasion by P falciparum.
[citation needed] Glucose-6-phosphate dehydrogenase (G6PD) is an important enzyme in red cells, metabolizing glucose through the pentose phosphate pathway, an anabolic alternative to catabolic oxidation (glycolysis), while maintaining a reducing environment.
Since mature red blood cells lack nuclei and cytoplasmic RNA, they cannot synthesize new enzyme molecules to replace genetically abnormal or ageing ones.
[citation needed] In 1956 Alving and colleagues showed that in some African Americans the antimalarial drug primaquine induces hemolytic anemia, and that those individuals have an inherited deficiency of G6PD in erythrocytes.
These qualitative defects create a red blood cell membrane that is less tolerant of shear stress and more susceptible to permanent deformation.
[citation needed] SAO is associated with protection against cerebral malaria in children because it reduces sequestration of erythrocytes parasitized by P. falciparum in the brain microvasculature.
Higher efficiency of sequestration via CD36 in SAO individuals could determine a different organ distribution of sequestered infected red blood cells.
[50] Plasmodium vivax has a wide distribution in tropical countries, but is absent or rare in a large region in West and Central Africa, as recently confirmed by PCR species typing.
[51] This gap in distribution has been attributed to the lack of expression of the Duffy antigen receptor for chemokines (DARC) on the red cells of many sub-Saharan Africans.
[57] Because of these several reports from different parts of the world it is clear that some variants of P. vivax are being transmitted to humans who are not expressing DARC on their red cells.
Human leucocyte antigen (HLA) polymorphisms common in West Africans but rare in other racial groups are associated with protection from severe malaria.
The studies suggest that the unusual polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
[64] He formalised in a technical paper published in 1949 in which he made a prophetic statement: "The corpuscles of the anaemic heterozygotes are smaller than normal, and more resistant to hypotonic solutions.
However, the same GWA association in two populations is powerful evidence that the single gene conferring strongest innate resistance to falciparum malaria is that encoding HbS.
[citation needed] The fitnesses of different genotypes in an African region where there is intense malarial selection were estimated by Anthony Allison in 1954.
