Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state

Fairhurst, Rick M.; Fujioka, Hisashi; Hayton, Karen; Collins, Kathleen F.; Wellems, Thomas E.

doi:10.1182/blood-2002-10-3105

Cited by 87 publications

(75 citation statements)

References 38 publications

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“…26,27 In the case of HbC, the mechanism of protection has been associated with reduced permissiveness of HbC erythrocytes to parasite replication. 28 G6PD deficiency, which can result in stress-induced hemolysis, also appears to protect against malaria in the heterozygous and hemizygous states. 29 The protective effect of G6PD deficiency may be caused by the reduction of intracellular parasite growth, increased elimination of infected RBCs, and increased fragility to malaria-induced oxidative damage.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Min‐Oo

Fortin

et al. 2004

Genes Immun

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The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61 show important splenomegaly prior to infection caused by the expansion of the red pulp, and display histological signs of extramedullary erythropoiesis in the liver. Examination of splenic cell populations by flow cytometry demonstrates elevated numbers of TER119-positive erythroid precursor cells (430% of total spleen cells), while RNA expression studies show elevated expression of erythrocyte-specific transcripts such as globin, transferrin receptor, and Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both strains is consistent with the presence of anemia as evidenced by low total erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of circulating reticulocytes (15-20%). These results strongly suggest that the mutant Pklr allele (Pklr 269A ) of AcB55/61 strains causes hemolytic anemia compensated by constitutive erythropoiesis, which in turn protects the mice against P. chabaudi infection. The possible molecular basis of the Pklr protective effect is discussed and is under current investigation in these two strains.

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Section: Discussionmentioning

confidence: 99%

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Min‐Oo

Fortin

et al. 2004

Genes Immun

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“…HbC heterozygotes have been shown to be protected against cerebral malaria (9,17) but are unlikely to enjoy as much of an advantage as ␤ S heterozygotes, who are strongly protected against all forms of severe malaria (9). However, the homozygous state is relatively mild (as a hematological condition) and appears also to offer protection against malaria (18,19). For these reasons, HbC Fig.…”

Section: Resultsmentioning

confidence: 99%

Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean

Penman

Pybus

Weatherall

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Several human genetic disorders of hemoglobin have risen in frequency because of the protection they offer against death from malaria, sickle-cell anemia being a canonical example. Here we address the issue of why this highly protective mutant, present at high frequencies in subSaharan Africa, is uncommon in Mediterranean populations that instead harbor a diverse range of thalassemic hemoglobin disorders. We demonstrate that these contrasting profiles of malaria-protective alleles can arise and be stably maintained by two well-documented phenomena: an alleviation of the clinical severity of ␣-and ␤-thalassemia in compound thalassemic genotypes and a cancellation of malaria protection when ␣-thalassemia and the sickle-cell trait are coinherited. The complex distribution of globin mutants across Africa and the Mediterranean can therefore be explained by their specific intracellular interactions.epistasis ͉ host genetics ͉ malaria ͉ thalassemia ͉ human evolution

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“…This is further supported by evidence of a positive selection, 9,10 and by in vitro studies with human cells. [11][12][13][14] Although the molecular mechanisms behind the protection remain to be elucidated, several mechanisms have been proposed: (i) a low capacity of the parasite to replicate in red blood cells; (ii) an altered expression of parasite antigens on the surface of red blood cells leading to a diminished cytoadhesion and/or an altered immune response; (iii) and an increased phagocytosis of the infected red blood cells. Several studies have demonstrated in vitro that the growth of the parasite was inhibited in CC cells, [12][13][14] whereas the parasite grows normally in AC cells.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] Although the molecular mechanisms behind the protection remain to be elucidated, several mechanisms have been proposed: (i) a low capacity of the parasite to replicate in red blood cells; (ii) an altered expression of parasite antigens on the surface of red blood cells leading to a diminished cytoadhesion and/or an altered immune response; (iii) and an increased phagocytosis of the infected red blood cells. Several studies have demonstrated in vitro that the growth of the parasite was inhibited in CC cells, [12][13][14] whereas the parasite grows normally in AC cells. 12 Recently, Fairhurst et al showed that AC and CC cells have a reduced capacity of adhesion to endothelial monolayers expressing CD36 and ICAM-1, rosetting interactions with non-infected red blood cells, and agglutination in the presence of pooled sera from malaria-immune adults, and an altered expression of PfEMP-1 on the membrane.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated in vitro that the growth of the parasite was inhibited in CC cells, [12][13][14] whereas the parasite grows normally in AC cells. 12 Recently, Fairhurst et al showed that AC and CC cells have a reduced capacity of adhesion to endothelial monolayers expressing CD36 and ICAM-1, rosetting interactions with non-infected red blood cells, and agglutination in the presence of pooled sera from malaria-immune adults, and an altered expression of PfEMP-1 on the membrane. These findings suggest that HbC may protect against cerebral malaria by inhibiting PfEMP-1-mediated sequestration in cerebral microvessels.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

et al. 2011

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Hemoglobin C (HbC) has been recently associated with protection against Plasmodium falciparum malaria. It is thought that HbC influences the development of immune responses against malaria, suggesting that the variation at the HbC locus (rs33930165) may interact with polymorphic sites in immune genes. We investigated, in 198 individuals belonging to 34 families living in Burkina Faso, statistical interactions between HbC and 11 polymorphisms within interleukin-4 (IL4), IL12B, NCR3, tumor necrosis factor (TNF) and lymphotoxin-a (LTA), which have been previously associated with malaria-related phenotypes. We searched for multilocus interactions by using the pedigree-based generalized multifactor dimensionality reduction approach. We detected 29 multilocus interactions for mild malaria, maximum parasitemia or asymptomatic parasitemia after correcting for multiple tests. All the single-nucleotide polymorphisms studied are included in several multilocus models. Nevertheless, most of the significant multilocus models included IL12B 3 0 untranslated region, IL12Bpro or LTA þ 80, suggesting that those polymorphisms play a particular role in the interactions detected. Moreover, we identified six multilocus models involving NCR3 that encodes the activating natural killer (NK) receptor NKp30, suggesting an interaction between HbC and genes involved in the activation of NK cells. More generally, our findings suggest an interaction between HbC and genes influencing the activation of effector cells for phenotypes related to mild malaria.

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Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state

Cited by 87 publications

References 38 publications

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

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