Resistance of glucose-6-phosphate dehydrogenase deficiency to malaria: Effects of fava bean hydroxypyrimidine glucosides on Plasmodium falciparum growth in culture and on the phagocytosis of infected cells

The balanced polymorphism of glucose-6-phosphate dehydrogenase deficiency (G6PD^-) is believed to have evolved through the selective pressure of malaria combined with consumption of fava beans. The implicated fava bean constituents are the hydroxypyrimidine glucosides vicine and convicine, which upon hydrolysis of their β-O-glucosidic bond, become potent pro-oxidants. In this work we show that the glucosides inhibit the growth of Plasmodium falciparum, increase the hexose-monophosphate shunt activity and the phagocytosis of malaria-infected erythrocytes. These activities are exacerbated in the presence of β-glucosidase, implicating their pro-oxidant aglycones in the toxic effect, and are more pronounced in infected G6PD^- erythrocytes. These results suggest that G6PD^- infected erythrocytes are more susceptible to phagocytic cells, and that fava bean pro-oxidants are more efficiently suppressing parasite propagation in G6PD^- erythrocytes, either by directly affecting parasite growth, or by means of enhanced phagocytic elimination of infected cells. The present findings could account for the relative resistance of G6PD^- bearers to falciparum malaria, and establish a link between dietary habits and malaria in the selection of the G69D^- genotype.