Inherited glutathione reductase deficiency and Plasmodium falciparum malaria--a case study.
In Plasmodium falciparum-infected red blood cells (RBCs), the flavoenzyme glutathione reductase (GR) regenerates reduced glutathione, which is essential for antioxidant defense. GR utilizes NADPH produced in the pentose phosphate shunt by glucose-6-phosphate dehydrogenase (G6PD). Thus, conditions affecting host G6PD or GR induce increased sensitivity to oxidants. Hereditary G6PD deficiency is frequent in malaria endemic areas and provides protection against severe malaria. Furthermore, GR deficiency resulting from insufficient saturation of the enzyme with its prosthetic group FAD is common. Based on these naturally occurring phenomena, GR of malaria parasites and their host cells represent attractive antimalarial drug targets. Recently we were given the opportunity to examine invasion, growth, and drug sensitivity of three P. falciparum strains (3D7, K1, and Palo Alto) in the RBCs from three homozygous individuals with total GR deficiency resulting from mutations in the apoprotein. Invasion or growth in the GR-deficient RBCs was not impaired for any of the parasite strains tested. Drug sensitivity to chloroquine, artemisinin, and methylene blue was comparable to parasites grown in GR-sufficient RBCs and sensitivity towards paraquat and sodium nitroprusside was only slightly enhanced. In contrast, membrane deposition of hemichromes as well as the opsonizing complement C3b fragments and phagocytosis were strongly increased in ring-infected RBCs of the GR-deficient individuals compared to ring-infected normal RBCs. Also, in one of the individuals, membrane-bound autologous IgGs were significantly enhanced. Thus, based on our in vitro data, GR deficiency and drug-induced GR inhibition may protect from malaria by inducing enhanced ring stage phagocytosis rather than by impairing parasite growth directly.
Gallo
Valentina
V
Dipartimento di Genetica, Biologia e Biochimica, University of Turin, Turin, Italy.
Schwarzer
Evelin
E
Rahlfs
Stefan
S
Schirmer
R Heiner
RH
van Zwieten
Rob
R
Roos
Dirk
D
Arese
Paolo
P
Becker
Katja
K
D016022:Case-Control Studies; D003176:Complement C3 / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000172:deficiency* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000150:complications* / Q000201:enzymology*; D008875:Middle Aged; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000378:metabolism
D003176:Complement C3; D007074:Immunoglobulin G; D005980:Glutathione Reductase; D005978:Glutathione