Human genetic resistance to malaria - Wikipedia
We studied the relationship between SCA and malaria in 2 groups of case patients. . Millennium Development Goals and all-cause under-5 mortality begins to fall. . Sickle cell trait and the risk of Plasmodium falciparum malaria and other. Secondary objectives were to calculate the effects of age and comorbidities on Correlation between prevalence of sickle cell trait and malaria. Protective Effect of Sickle Cell Trait Against Malaria-Associated Mortality Most earlier studies of the relationship between sickle cell trait and.
Higher efficiency of sequestration via CD36 in SAO individuals could determine a different organ distribution of sequestered infected red blood cells. These provide a possible explanation for the selective advantage conferred by SAO against cerebral malaria.
Duffy antigen system 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. However, observations have accumulated showing that the original Miller report needs qualification.
In human studies of P. Genotyping indicated that multiple P. The authors suggest that among Malagasy populations there are enough Duffy-positive people to maintain mosquito transmission and liver infection. More recently, Duffy negative individuals infected with two different strains of P.
The frequency of such transmission is still unknown. The same phenomenon has been observed in New World monkeys. The distribution of Duffy negativity in Africa does not correlate precisely with that of P. The potency of P. DARC negativity remains a good example of innate resistance to an infection, but it produces a relative and not an absolute resistance to P. Old World distribution of enzymopathies and immunogenetic variants Gerbich antigen receptor negativity[ edit ] Main article: Gerbich antigen system The Gerbich antigen system is an integral membrane protein of the erythrocyte and plays a functionally important role in maintaining erythrocyte shape.
It also acts as the receptor for the P.How is malaria related to sickle cell anemia
There are four alleles of the gene which encodes the antigen, Ge-1 to Ge Three types of Ge antigen negativity are known: Such individuals have a subtype of a condition called hereditary elliptocytosischaracterized by oval or elliptical shape erythrocytes. Other rare erythrocyte mutations[ edit ] Rare mutations of glycophorin A and B proteins are also known to mediate resistance to P. Human leucocyte antigen polymorphisms[ edit ] Main article: Human leukocyte antigen Human leucocyte antigen HLA polymorphisms common in West Africans but rare in other racial groups, are associated with protection from severe malaria.
This group of genes encodes cell-surface antigen-presenting proteins and has many other functions. In West Africa, they account for as great a reduction in disease incidence as the sickle-cell hemoglobin variant. The studies suggest that the unusual polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Polymorphisms at the HLA loci, which encode proteins that participate in antigen presentation, influence the course of malaria. Haldane was the first to give a hypothesis on the relationship between malaria and the genetic disease. 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: 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: Introduction Early 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. Falciparum to develop in HbS-contaning red cells and is also rare to find an HbS carrier struck by cerebral malaria, a common cause of death in this disease.
The gradual increase in HbS allele frequencies from epidemic areas to endemic areas in Africa is consistent with the hypothesis that malaria protection by HbS involves the enhancement of both innate and acquired immunity to P.
Falciparum; interactions with haemoglobin C might explain the lower HbS allele frequencies in West Africa.
Sickle Cell Disease: New Opportunities and Challenges in Africa
The quantity and orientation of aligned sickle hemoglobin polymers AHP in sickle cells probably play an important role in the flow of sickled RBC through the circulation: It is in the first place important to realize that invasion of red cells by parasitic merozoites is a multi-step process, involving interactions between genetic, biochemical and immunological determinants; we may therefore take into account the following factors.
Genetic factors Many factors of genetic character may be involved in the mechanism of protection. A number of studies have been focused on different components of the red cell membrane and special attention was given to the role of complement regulatory proteins, particularly complement receptor 1 CR1. Complement receptor-1 polymorphism associated with resistance to severe malaria was also demonstrated in Kenya.
Falciparum merozoites possessing the peculiar erytrocye-binding antigen. It has also ben confirmed that Gerbich antigens act as receptors for the malarial parasite Plasmodium falciparum, while reduced levels of GPC and GPD are associated with hereditary elliptocytosis.
However the role of the CD36 gene in malaria is still debated and no confirmation was obtained more recently. As the involvement of host genetic factors is receiving increased attention, there is now a trend to set up genome-wide studies to identify malaria resistance genes that determine the structure or function of red blood cells. In this context it is interesting to consider a genome-wide linkage and association study for P.
Moreover, one gene associated with malaria infection was found in the 5q31q33 region. Role of sickling It is of interest that malaria might act as a trigger for intravascular sickling: Slow deoxygenation results in a single fiber domain that initially grows in one general direction, with the classic sickled shape resulting from oblique alignment of adjacent fibers through interactions of their helical surfaces; 40 in contrast, rapid deoxygenation produces cells that do not appear sickled at all, having a nearly normal biconcave disc shape, even though the cells are filled with multiple domains of polymerized hemoglobin.
While cytotoxic per se, labile iron induces the expression of ferritin H chain FtHwhich confers cytoprotection against free heme in vitro. The existence of a multiple hit system, by which free heme synergizes with other cytotoxic agonists, e. There is therefore a special form of immune regulation, which may explain the protective effect of sickle cell trait against severe malaria.
A traditional definition of tolerance in microbiological terms is the capacity to limit the obnoxious action of a parasite or microbe burden: It thus appears that both tolerance and resistance are opposite factors which may control the effect of a pathogenic agent.
Development of tolerance is also based on immunologic factors, although the mechanisms of tolerance are still not well understood, particularly in animal hosts; however a recent report describes a mechanism of host tolerance during infection with Plasmodium parasites, showing that the heme detoxification activity of HO-1 is a critical component of host tolerance to Plasmodium infection-associated liver failure.
Following previous reports using different mouse and Plasmodium strains, 62 it was found that survival advantage occurs irrespectively of parasite load and is apparently not associated with parasite sequestration in different organs, confirming induction of tolerance by sickle human Hb to Plasmodium infection.
As type I interferons can cause immune pathology, the role of the STING-TBK1-type I interferon pathway was examined in a mouse model of cerebral malaria, and genetic ablation of type-1 interferon pathway resulted in protection from diseas. The latest example of interactions between different pathways comes from a very recent study by Schuldt et al.
As C promotes apoptosis, this effect may be ascribed to a C —aided killing of immune cells, thus preventing an excessive immune response, another case of molecular-immunological interplay still waiting to be clarified.
Sickle cell protection from malaria
It is finally worthwhile to emphasize the importance of the study of the natural mechanisms of defense as the basis for numerous attempts to develop vaccines, which may either prevent the development of malaria at all or reduce its major complications: Falciparum in humans, namely the pre-erythrocytic stage, which initiates the infection; the asexual blood stage, which causes disease; and the gametocyte stage, which infects mosquitoes that transmit the parasite.
Hematologic and genetic studies on the transmission of Thalassemia minor Mediterranean anemia Arch Int Med. The rate of mutation of human genes. Population genetics of haemoglobin variants, thalassaemia and glucosephosphate dehydrogenase deficiency, with particular reference to the malaria hypothesis. Bull World Health Organ.
Protective Effect of Sickle Cell Trait Against Malaria-Associated Mortality And Morbidity
Increased sickling of parasitised erythrocytes as mechanism of resistance against malaria in the sickle-cell trait. Ruwende C, Hill A. Glucosephosphate dehydrogenase deficiency and malaria. Am J Trop Med Hyg. Haemoglobin C protects against clinical falciparum malaria. Pyruvate kinase deficiency and malaria. New Engl J Med. Proc Assoc Am Physicians. Sickle cell disease in northern Rhodesia. East Afr Med J.
The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Polymorphism and natural selection in human populations. Hemoglobin variants and disease manifestations in severe falciparum malaria. Human red blood cell polymorphisms and malaria. Population structure of Sicily: