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

Abstract

Sickle cell trait (AS) confers partial protection against lethal malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.

A Mild and Versatile Friedel–Crafts Methodology for the Diversity‐Oriented Synthesis of Redox‐Active 3‐Benzoylmenadiones with Tunable Redox Potentials

“…This bioactivation process was also reported for the anticancer quinonic mitomycin C . It is well documented that, although the concentration of O 2 in arterial blood is approximately 13 %, O 2 concentrations below 7.5 % are found in most organs to which Plasmodium ‐parasitized red blood cells sequester, including the bone marrow, brain, and liver . Therefore, in the hypoxic conditions where malaria parasites can survive, the half‐life of NQH .…”

“…[6] This bioactivation process wasa lso reported for the anticancer quinonic mitomycin C. [43] It is well documented that, although the concentration of O 2 in arterial bloodi sa pproximately 13 %, O 2 concentrations below 7.5 %a re found in most organs to which Plasmodiumparasitized red blood cells sequester,i ncluding the bone marrow,b rain, and liver. [44] Therefore, in the hypoxicc onditions where malaria parasites can survive, the half-life of NQHC might be extended, allowing it to participate in severalm etabolic transformations, such as the benzylic oxidation (Scheme 10). Thus, after transport to the parasitic compartment, NQHC can undergo further reduction by other key protein targets to produce the toxic NQH 2 (Scheme 10).…”

Genetic markers associated with antimalarial drug resistance and haemoglobin genotypes among malaria patients in Kaduna State, Nigeria

“…This suggests that individuals with HbAS and HbAC are probably able to resist malaria better than HbAA. This is in agreement with the ndings of Aidoo et al [41], Ayi et al [42], Williams et al [43], Albiti and Nsiah [40] and Archer et al [44]. In another study by Williams et al [45], HbAS was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria.…”

Human genetics and malaria resistance

“…Furthermore, impaired parasite growth and development in HbAS RBCs has also been reported (McAuley et al 2010;Komba et al 2009;Makani et al 2010), with one recent study demonstrating that oxygen-dependent polymerization of HbS is responsible for P. falciparum growth inhibition (Archer et al 2018). Finally, immune-mediated protective mechanisms have also been postulated for HbAS, as well as α-and β-thalassaemias, and G6PD deficiency.…”