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Can nature's defence against malaria be mimicked by the development of host-directed therapies?

The Pharmacogenomics Journal volume 4, pages 141–142 (2004)Cite this article

There is an evolutionary battle being fought and the battleground is the humble erythrocyte. The two foes are the genomes of the malarial parasites and their human host and the battle has been waging since the beginning of vertebrate evolution. On the one hand, the erythrocyte must ensure the oxygenation of tissues through its transport of oxygen and yet, on the other, it supplies the malarial parasite with an essential home during the prolonged blood-stage of the life cycle of this most ferocious of human pathogens.

Polymorphisms within red cell genes reflect past and present actions between the parasite and host. Host genetics has changed many genes encoding red cell proteins rendering an advantage to the host over the parasite. However, many of these changes have come at a cost. Many of the hemoglobinopathies are lethal in the homozygous state yet presumably offer protection to heterozygotes which would explain the geographic coincidence between the thalassemias, HbS and malaria. Melanesian ovalocytosis is caused by a mutation in the erythrocyte band 3 gene (SLC4A1). The homozygous mutation is an embryonic lethal yet the frequency of the mutation can be as great as 30–40% in some regions of Papua New Guinea (PNG), suggesting a strong selection on carriers.1 In fact, it is the deleterious homozygous state that has brought many of these mutations to the attention of geneticists, resulting in their being implicated in the host response to malaria. It is possible, and indeed likely that there are other host factors contributing to disease resistance where homozygosity is unremarkable. A mutation in the promoter of the Duffy gene (FY) abrogates expression of the Duffy protein in the red cell. The Duffy protein is the only entry molecule the red cell has for the malarial parasite Plasmodium vivax.2 This mutation has no obvious homozygous phenotype and as a result has been fixed in many African populations resulting in the virtual absence of vivax malaria from this continent. Similarly, the glycophorin C molecule offers one of many portals of entry for P. falciparum into the erythrocyte and, not surprisingly there are populations in PNG where the expression of the glycophorin C gene (GYPC) is lost.3 The Gerbich blood group appears to be the only resultant phenotype.

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  1. Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

    S J Foote

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  1. S J Foote
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Correspondence to S J Foote.

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Foote, S. Can nature's defence against malaria be mimicked by the development of host-directed therapies?. Pharmacogenomics J 4, 141–142 (2004). https://doi.org/10.1038/sj.tpj.6500241

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