Malaria & Red Cell Disorders SK Cheong Faculty of Medicine - PowerPoint PPT Presentation

Malaria & Red Cell Disorders SK Cheong Faculty of Medicine & Health Sciences, Universiti Tunku Abdul Rahman (UTAR) Bandar Sungai Long, Selangor

On the Origin of Species  Charles Darwin, FRS  Born 12 th Feb 1809  Published the above book in 1859  Survival of human species – genetic resistance to malaria

Evolutionary Anti-Malarial Strategies  Inhibit intracellular growth  Inhibit of release of mature merozoites  Inhibit entry into red cells  Promotion of phagocytosis & immune clearance of infected red cells  Prevention of vascular or blood cells adherence of infected red cells

Consequence of Selection  Emergence of rare RBC genes  In malarial zones  Lessen malaria morbidity & mortality

Evidence of selection as illustrated by inherited red cell disorders

Thalassaemias & Haemoglobinopathy

Other Lines of Evidence  Binding of malaria hyperimmune serum to plasmodium infected thalassemic rbc – more antibodies per unit area  Hb F inhibit growth & development of malarial parasites  Young alpha-thalassemics show susceptibilty to non-lethal malarial parasitemia – cross species protection

ASH Annual Scientific Meeting, 2002, Education Handbook, Page 35-57

G-6-P-D Deficiency

Mechanisms of Protection  Not clearly understood  Both hemizygote male and heterozygote female are protected  Studies suggested impaired parasite growth or more efficient phagocytosis of parasitised red cells Cook GS, Hill AVS. Nat Rev Genet. 2001; 2:967- 77; Ruwende C et al. Nature; 1995:376:246-9.

Hereditary Ovalocytosis

Cytoskeletal Membrane Defect

Mutation in Band 3  Fully susceptible to plasmodium invasion  Complete protection against cerebral malaria  Parasite-vascular interaction  Interaction remains to be characterized Genton B et al. Nature 1995; 378: 564-5. Allen SJ et al. Am J Trop Med Hyg 1999; 60:1056-60

Red Cell Surface Antigens

Louis Miller described the Duffy story in Africans way back in 1976

Duffy Antigen  Duffy negative individuals in Africa – protected against P. vivax  P. vivax rbc entry mediated through DARC Toumamile C et al. Nature 1995; 10:224-8; Miller LH et al N Engl J Med 1976; 295:302-4

Glycophorin A  MNS blood group  RBC trans-memberane proteins  Wright b (Wrb) antigen located on Glycophrin A – receptor for P. falciparum  Cells lacking Glycophrin A are resistant to invasion by P vivax Ridgewell K et al. Biochem J. 1983; 209:273-6; Facer CA. Bull Soc Pathol Exot Filiales. 1983; 76:463-9

Glycophorin B (GYPB)  Also bears the antigenic determinants of MNS blood groups  Found to act as receptor for erythrocyte binding protein 175 (EBA 175) of P falciparum  RBCs deficient in GYPB (e.g. Dantu, S- s-u rbcs) are resistant to P. falciparum. Field SP et al. Hum Genet. 1994; 93: 148-50 .

Louis Miller’s group found another entry route for P. falciparum in 2009

EBL1  One of the P. falciparum erythrocyte binding proteins  Bind to GYPB  RBCs deficient in GYPB are resistant to invasion by P. falciparum Mayer DC et al. Proc Natl Acad Sci USA 2009; 106:5348-52 .

Efe Pygmies from Ituri Forest

59% of Efe pygmies have GYPB deficient RBCs. Bercelloti GM. The Hematologists 2009; 6(4): 8