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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

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Malaria & Red Cell Disorders

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

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On the Origin of Species

 Charles Darwin, FRS  Born 12th Feb 1809  Published the above

book in 1859

 Survival of human

species – genetic resistance to malaria

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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

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Consequence of Selection

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

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Evidence of selection as illustrated by inherited red cell disorders

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Thalassaemias & Haemoglobinopathy

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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

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

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G-6-P-D Deficiency

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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.

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Hereditary Ovalocytosis

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Cytoskeletal Membrane Defect

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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

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Red Cell Surface Antigens

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

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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

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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

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Glycophorin B (GYPB)

 Also bears the antigenic determinants

f 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.

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

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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.

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Efe Pygmies from Ituri Forest

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59% of Efe pygmies have GYPB deficient RBCs.

Bercelloti GM. The Hematologists 2009; 6(4): 8

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