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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2527-2534
Early Phagocytosis of Glucose-6-Phosphate Dehydrogenase
(G6PD)-Deficient Erythrocytes Parasitized by Plasmodium
falciparum May Explain Malaria Protection in G6PD Deficiency
Marina Cappadoro,
Giuliana Giribaldi,
Estella O'Brien,
Franco Turrini,
Franca Mannu,
Daniela Ulliers,
Gino Simula,
Lucio Luzzatto, and
Paolo Arese
From the Dipartimento di Genetica, Biologia, Biochimica,
Università di Torino, Torino, Italy; and the Department of
Haematology, Royal Postgraduate School of Medicine,
Hammersmith Hospital, London, UK.
In population-based studies it has been established that inherited
deficiency of erythrocyte (E) glucose-6-phosphate dehydrogenase (G6PD)
confers protection against severe Plasmodium falciparum (P
falciparum) malaria. Impaired growth of parasites in G6PD-deficient E in vitro has been reported in some studies, but not in others. In a
systematic analysis, 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 either normal or G6PD-deficient (Mediterranean
variant) E. With all of these strains and at different maturation
stages, we were unable to detect any difference in the amount of P
falciparum-specific G6PD mRNA in normal versus deficient
parasitized E. The rate of 14C-CO2 production
from D-[1-14C] glucose (which closely reflects
intracellular activity of G6PD) contributed by the parasite was very
similar in intact normal and deficient E. By contrast, in studies of
phagocytosis of parasitized E by human adherent monocytes, we found
that when the parasites were at the ring stage (ring-stage parasitized
E [RPE]), deficient RPE were phagocytosed 2.3 times more intensely
than normal RPE (P = .001), whereas there was no difference
when the parasites were at the more mature trophozoite stage
(trophozoite-stage parasitized E [TPE]). Phagocytic removal markers
(autologous IgG and complement C3 fragments) were significantly higher
in deficient RPE than in normal RPE, while they were very similar in
normal and deficient TPE. The level of reduced glutathione was
remarkably lower in deficient RPE compared with normal RPE. We conclude
that impaired antioxidant defense in deficient RPE may be responsible
for membrane damage followed by phagocytosis. Because RPE, unlike TPE,
are nontoxic to phagocytes, the increased removal by phagocytosis of
RPE would reduce maturation to TPE and to schizonts and may be a highly
efficient mechanism of malaria resistance in deficient subjects.
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