Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

Abstract

Plasmodium falciparum infections can cause severe malaria, but not every infected person develops life-threatening complications. In particular, carriers of the structural haemoglobinopathies S and C and infants are protected from severe disease. Protection is associated with impaired parasite-induced host actin reorganization, required for vesicular trafficking of parasite-encoded adhesins, and reduced cytoadherence of parasitized erythrocytes in the microvasculature. Here we show that aberrant host actin remodelling and the ensuing reduced cytoadherence result from a redox imbalance inherent to haemoglobinopathic and fetal erythrocytes. We further show that a transient oxidative insult to wild-type erythrocytes before infection with P. falciparum induces the phenotypic features associated with the protective trait of haemoglobinopathic and fetal erythrocytes. Moreover, pretreatment of mice with the pro-oxidative nutritional supplement menadione mitigate the development of experimental cerebral malaria. Our results identify redox imbalance as a causative principle of protection from severe malaria, which might inspire host-directed intervention strategies.

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

“…Some studies have observed that parasites can grow normally in AS RBCs at 3% and 5% O 2 (19,(38)(39)(40). This may be due to technical differences in culture format and growth assessments.…”

Hemoglobin variants shape the distribution of malaria parasites in human populations and their transmission potential

“…These two hemoglobin variants have been associated with protection against severe malaria syndromes in numerous epidemiological studies 4 , and mechanistic hypotheses proposed to explain this protection include impaired blood stage parasite development 5 – 7 , reduced cytoadherence of infected red blood cells 8 , 9 , which is linked to the redox imbalance of hemoglobinopathies and its effects on the export of parasite-encoded proteins 10 , 11 , tolerance to malaria infection related to heme catabolism by heme oxygenase-1 12 , or accelerated acquisition of immunity 13 – 15 . Life-threatening episodes, however, represent only a small proportion of falciparum infections 16 , including in susceptible individuals 1 , and these same mechanisms might regulate other epidemiologically important parameters in non-severe infections, such as duration of parasite carriage and infectiousness.…”

Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria

“…In support of this latter hypothesis, two recently-published studies have shown that in static adhesion assays, VAR2CSA-expressing FCR3 parasites in HbAS and HbAC erythrocytes exhibit significant reductions in adherence to CSA compared to those grown in HbAA erythrocytes, this decreased binding being much greater for parasitized HbAC than HbAS erythrocytes 26, 27 . However, these studies assessed only a single parasite strain in static but not flow adhesion assays.…”