Abstract
A linkage between presence of Sickle Haemoglobin (HbS) and protection from malaria infection and clinical manifestations in certain areas was suspected from early observations and progressively elucidated by more recent studies. Research has confirmed the abovementioned connection, but also clarified how such protection may be abolished by coexistence of sickle cell trait (HbS trait) and alpha thalassemia, which may explain the relatively low incidence of HbS trait in the Mediterranean. The mechanisms of such protective effect are now being investigated: factors of genetic, molecular and immunological nature are prominent. As for genetic factors attention is given to the role of the red blood cell (RBC) membrane complement regulatory proteins as polymorphisms of these components seem to be associated with resistance to severe malaria; genetic ligands like the Duffy group blood antigen, necessary for erythrocytic invasion, and human protein CD36, a major receptor for P. falciparum-infected RBC's, are also under scrutiny: attention is focused also on plasmodium erythrocyte-binding antigens, which bind to RBC surface components. Genome-wide linkage and association studies are now carried out too, in order to identify genes associated with malaria resistance. Only a minor role is attributed to intravascular sickling, phagocytosis and haemolysis, while specific molecular mechanisms are the object of intensive research: among these a decisive role is played by a biochemical sequence, involving activation of haeme oxygenase (HMO-1), whose effect appears mediated by carbon monoxide (CO). A central role in protection from malaria is also played by immunological factors, which may stimulate antibody production to plasmodium antigens in the early years of life; the role of agents like pathogenic CD8 T-cells has been suggested while the effects of molecular actions on the immunity mechanism are presently investigated. It thus appears that protection from malaria can be explained by interaction of different factors: the elucidation of such mechanisms may prove valuable for the prevention and treatment strategy of a disease which still affects large parts of the world.
Highlights
Suggestions of a possible relationship between extension and prevalence of haemoglobinopathies in some Mediterranean areas and malaria infection date back to the late 40’s.1,2 It was thereafter widely agreed that red cell genetic disorders, like Thalassemia, Sickle cell Disease and Glucose-6-phosphate dehydrogenase deficiency (G6PD) may confer resistance to Plasmodium infection.[3,4,5] A special role in preventing complications of severe malaria has been postulated for HbC.[6]
Among other genic interaction between Hbpathic patients it is of interest to examine West African populations, in which the HbS carrier state was found to be negatively associated with all major forms of severe P. falciparum malaria, while the negative associations of the carrier states of HbC and alphathalassemia appeared to be limited to cerebral malaria and severe anemia, respectively; as for HbC, protection from malaria is enjoyed by heterozygotes but to a lesser degree than βS heterozygots; a slight protection offered to homozygotes may explain the persistence and even a minimal increase of HbC in these regions.[13]
Another line of investigation focused on the human protein CD36, which is a major receptor for P. falciparum-infected red blood cells[30] (RBC’s) and may contribute to the disease by sequestering infected red blood cells30 (RBC’s) and inhibiting the immune response to the parasite so that the acquisition of immune responses that kill parasites is delayed through modulation of the function of antigen-presenting cells:[31] it was found by Aitman et al.[32] that African populations contain an exceptionally high frequency of mutations in CD36 and that these mutations, which cause CD36 deficiency, are associated with susceptibility to severe malaria; this may suggest that CD36 was a determinant of the risk of developing cerebral malaria (CM) as compared to other severe malaria complications
Summary
Suggestions of a possible relationship between extension and prevalence of haemoglobinopathies in some Mediterranean areas and malaria infection date back to the late 40’s.1,2 It was thereafter widely agreed that red cell genetic disorders, like Thalassemia, Sickle cell Disease and Glucose-6-phosphate dehydrogenase deficiency (G6PD) may confer resistance to Plasmodium infection.[3,4,5] A special role in preventing complications of severe malaria has been postulated for HbC.[6]. Suggestions of a possible relationship between extension and prevalence of haemoglobinopathies in some Mediterranean areas and malaria infection date back to the late 40’s.1,2. It was thereafter widely agreed that red cell genetic disorders, like Thalassemia, Sickle cell Disease and Glucose-6-phosphate dehydrogenase deficiency (G6PD) may confer resistance to Plasmodium infection.[3,4,5] A special role in preventing complications of severe malaria has been postulated for HbC.[6] Ovalocytosis, caused by a deletion in the band-3 gene, has shown to exert a strong protection from malaria in southeast Asia.[7] Beside G6PD, another red cell disorder from enzyme deficiency, like pyruvate kinase deficiency, has recently shown to interfere, as it was demonstrated that the most common mutation in the PKLR gene, protects red cells of the homozygote against the parasite in vitro.[8]. Falciparum to develop in HbS-contaning red cells and is rare to find an HbS carrier struck by cerebral malaria, a common cause of death in this disease.[13]
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