Early Phagocytosis of Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Erythrocytes Parasitized by Plasmodium falciparum May Explain Malaria Protection in G6PD Deficiency

Abstract

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 ofP 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.

Defectos eritrocíticos y densidad de la parasitemia en pacientes con malaria por Plasmodium falciparum en Buenaventura, Colombia

“…La coincidencia geográfica mencionada apoya la teoría de que la malaria es un factor selectivo respecto a la presencia de defectos eritrocíticos. En el caso específico de la deficiencia de G6PD, las mujeres heterocigotas portadoras de esta deficiencia podrían estar protegidas contra la malaria causada por Plasmodium falciparum y las hemoglobinopatías confieren algún grado de protección contra la malaria grave por P. falciparum (4,6,7). Algunos estudios realizados en poblaciones africanas han mostrado una menor densidad de la parasitemia, que pareciera indicadora de esa protección o resistencia (8)(9)(10), mientras que otros parecen indicar que los defectos eritrocíticos innatos no confieren protección contra la malaria (11).…”

The Impact of Human Genetic Factors (G6pd and Type of Hemoglobin) on the Course of Uncomplicated Malaria Infection in Children Aged from 2 to 10 Years Living in the Banfora Health District in Burkina Faso

“…In a previous study in Burkina Faso, Ouattara et al (2014) showed that G6PD deficiency protect against asymptomatic malaria [15]. The same result was found in Gabon [26,25]. In a systematic review, [27] it was mentioned that that G6PD deficiency can potentially protect against uncomplicated malaria in African countries, but not severe malaria [27].…”

“…Impaired growth of parasites in G6PD-deficient erythrocyte in vitro has been reported in some studies, but not in others. In a rprevious report, Marina Cappadoro et al, 1998, it was showed that G6PD deficient erythrocyte parasitized were phagocytosed 2.3 times more intensely than normal [25]. In a previous study in Burkina Faso, Ouattara et al (2014) showed that G6PD deficiency protect against asymptomatic malaria [15].…”

O desafio da malária: o caso brasileiro e o que se pode esperar dos progressos da era genômica

“…Desidrogenase de Glicose-6-fosfato (G6PD) -Para seu desenvolvimento, o parasita aumenta consideravelmente sua necessidade metabólica, num período limitado de tempo, gerando um estresse adicional à célula hospedeira, levando-a à destruição. A membrana eritrocitária sofre modificações decorrentes desses processos oxidantes, levando a uma fagocitose acentuada dos eritrócitos em indivíduos thalassêmicos, com traço falcêmico e com deficiência em G6PD (Cappadoro et al, 1992). O gene da G6PD é ligado ao cromossomo X e apresenta numerosas mutações, que causam deficiência enzimática nos eritrócitos.…”