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. 2017 Jul 15;216(2):263-266.
doi: 10.1093/infdis/jix278.

Asian G6PD-Mahidol Reticulocytes Sustain Normal Plasmodium Vivax Development

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Free PMC article

Asian G6PD-Mahidol Reticulocytes Sustain Normal Plasmodium Vivax Development

Germana Bancone et al. J Infect Dis. .
Free PMC article

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in humans and appears to be protective against falciparum severe malaria. Controversially, it is also thought that Plasmodium vivax has driven the recent selection of G6PD alleles. We use an experimental approach to determine whether G6PD-MahidolG487A variant, a widespread cause of severe G6PD deficiency in Southeast Asia, provides a barrier against vivax malaria. Our results show that the immature reticulocytes (CD71+) targeted by P. vivax invasion are enzymatically normal, even in hemizygous G6PD-Mahidol G487A mutants; thus, allowing the normal growth, development, and high parasite density in severely deficient samples.

Keywords: Plasmodium vivax; glucose-6-phosphate dehydrogenase deficiency; reticulocytes.

Figures

Figure 1.
Figure 1.
CD71+ reticulocytes are phenotypically G6PD normal in subjects with Mahidol Mutation. A, G6PD activity detected by flow cytometry in erythrocytes, CD71 and CD71+ fraction of wild-type and G6PD-Mahidol mutant cord blood and in G6PD-Mahidol mutant peripheral blood. B, Quantification of G6PD activity (mean values ± SDs) for 4 wild-type cord blood, 3 G6PD-Mahidol–deficient cord blood, and 3 G6PD-Mahidol peripheral blood samples. C, G6PD activity detected by fluorescence microscopy in CD71 fraction of Mahidol mutant cord blood (scale bar represents 5 μm). D, G6PD activity time course detected by flow cytometry in CD71+ and CD71 erythrocytes. The red dotted line represents the limit of positivity for G6PD (separation between methemoglobin and oxyhemoglobin peaks of green fluorescence). E, Morphology of immunomagnetically sorted CD71+ and CD71 erythrocytes from wild-type and G6PD-Mahidol–mutant patients visualized by scanning electron microscopy. Scale bar represents 5 μm. F, G6PD kinetic activity in CD71+ and CD71 for wild-type and G6PD-Mahidol patients (n = 4) measured by flow cytometry during 5 days of culture at 37.5°C and 5% CO2 in McCoy medium 20% AB serum. The MFI of oxyhemoglobin for CD71+ reticulocytes at time 0 was assigned to be 100% of G6PD activity for each sample. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; MFI, mean fluorescence intensity.
Figure 2.
Figure 2.
Normal development of Plasmodium vivax in G6PD-Mahidol–mutant reticulocytes. A, Schematic of P. vivax growth assay in G6PD wild-type and G6PD-Mahidol–mutant reticulocytes. B, G6PD activity detected by fluorescence microscopy in ring and schizont stages 3 hours and 40 hours, respectively, after inoculation into nascent reticulocytes. C, P. vivax invasion in adult blood from 3 different genotypes (wild-type, and Mahidol homozygote and heterozygote) with 4 different field isolates. D, Proportion of late parasite stages after 48 hours of culture in G6PD wild-type and G6PD-Mahidol mutant (n = 3 for each genotype with 5 different P. vivax isolates; 48 hr postinvasion). In insert, Giemsa-stained thin film showing segmented vivax schizonts in G6PD-Mahidol–mutant reticulocytes (54 hr postinvasion). The scale represents 5 μm. E, Plasmodium vivax gametocyte frequency in wild-type and G6PD-Mahidol reticulocytes. In insert, Giemsa-stained thin film showing vivax gametocytes in G6PD-Mahidol–mutant reticulocytes (54 hr postinvasion). The scale represents 5 μm. F, Number of vivax merozoites per schizonts in wild type and G6PD-Mahidol–mutant CD71+ reticulocytes (n = 3 for each genotype with 3 different P. vivax isolates).

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References

    1. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371:64–74. - PubMed
    1. Huang Y, Choi MY, Au SW, Au DM, Lam VM, Engel PC. Purification and detailed study of two clinically different human glucose 6-phosphate dehydrogenase variants, G6PD(Plymouth) and G6PD(Mahidol): Evidence for defective protein folding as the basis of disease. Mol Genet Metab 2008; 93:44–53. - PubMed
    1. Pandolfi PP, Sonati F, Rivi R, Mason P, Grosveld F, Luzzatto L. Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J 1995; 14:5209–15. - PMC - PubMed
    1. Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. Br J Haematol 2014; 164:469–80. - PMC - PubMed
    1. Ruwende C, Khoo SC, Snow RW et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 1995; 376:246–9. - PubMed

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