EARLY PHAGOCYTOSIS OF GLUCOSE-6-PHOSPHATE-DEHYDROGENASE (G6PD)-DEFICIENT ERYTHROCYTES PARASITIZED BY PLASMODIUM-FALCIPARUM MAY EXPLAIN MALARIA PROTECTION IN G6PD DEFICIENCY

In population-based studies it has been established that inherited def iciency of erythrocyte (E) glucose-8-phosphate dehydrogenase (G6PD) co nfers protection against severe Plasmodium falciparum (P falciparum) m alaria. Impaired growth of parasites in G6PD-deficient E in vitro has been reported in some studies, but not in others. In a systematic anal ysis, we have found that with five different strains of P falciparum ( FCR-3, KI, C10, HB3B, and T9/96), there was no significant difference in either invasion or maturation when the parasites were grown in eith er normal or G6PD-deficient (Mediterranean variant) E. With all of the se strains and at different maturation stages, we were unable to detec t any difference in the amount of P falciparum-specific G6PD mRNA in n ormal versus deficient parasitized E. The rate of C-14-CO2 production from D-[1-C-14] glucose (which closely reflects intracellular activity of G6PD) contributed by the parasite was very similar in intact norma l and deficient E. By contrast, in studies of phagocytosis of parasiti zed E by human adherent monocytes, we found that when the parasites we re at the ring stage (ring-stage parasitized E [RPE]), deficient RPE w ere phagocytosed 2.3 times more intensely than normal RPE (P =.001), w hereas there was no difference when the parasites were at the more mat ure trophozoite stage (trophozoite-stage parasitized E [TPE]). Phagocy tic removal markers (autologous IgG and complement C3 fragments) were significantly higher in deficient RPE than in normal RPE, while they w ere very similar in normal and deficient TPE. The level of reduced glu tathione was remarkably lower in deficient RPE compared with normal RP E. We conclude that impaired antioxidant defense in deficient RPE may be responsible for membrane damage followed by phagocytosis. Because R PE, unlike TPE, are nontoxic to phagocytes, the increased removal by p hagocytosis of RPE would reduce maturation to TPE and to schizonts and may be a highly efficient mechanism of malaria resistance in deficien t subjects. (C) 1998 by The American Society of Hematology.