Multiple
glucose-6-phosphate dehydrogenase (G6PD)-deficient alleles have reached polymorphic frequencies because of the protection they confer against
malaria infection. A protection mechanism based on enhanced phagocytosis of parasitized G6PD-deficient erythrocytes that are oxidatively damaged is well accepted. Although an association of this phenotype with the impairment of the
antioxidant defense in
G6PD deficiency has been demonstrated, the dysfunctional pathway leading to membrane damage and modified exposure of the
malaria-infected red cell to the host is not known. Thus, in this study, erythrocytes from the common African variant
G6PD A- were used to analyze by redox proteomics the major oxidative changes occurring in the host
membrane proteins during the intraerythrocytic development of Plasmodium falciparum, the most lethal
malaria parasite. Fifteen carbonylated
membrane proteins exclusively identified in infected
G6PD A- red blood cells revealed selective oxidation of host
proteins upon malarial
infection. As a result, three pathways in the host erythrocyte were oxidatively damaged in
G6PD A-: (1) traffic/assembly of exported parasite
proteins in red cell cytoskeleton and surface, (2) oxidative stress defense
proteins, and (3) stress response
proteins. Additional identification of hemichromes associated with
membrane proteins also supports a role for specific oxidative modifications in protection against
malaria by G6PD polymorphisms.