Organism-like formation of Schistosoma hemozoin and its function suggest a mechanism for anti-malarial action of artemisinin

Abstract

The current theories of antimalarial mechanism of artemisinin are inadequate to fully explain the observed effects. In our study, “organism-like” formation of Schistosoma hemozoin granules by attaching to and utilizing erythrocytes to form new ones was observed. This indicates that heme iron is transferred from erythrocytes to hemozoin granules during their formation. However, as a disposal product of heme detoxification, these granules are not completely expelled from the Schistosoma gut, but decomposed again between microvilli in the posterior portion of the gut to transfer iron to eggs. Based on the function of iron transport supported by our observation of the unique process of Schistosoma hemozoin formation, here we propose a new viewpoint of antimalarial mechanism of artemisinin, which emphasizes the final outcome, i.e., interference of iron utilization in parasites by artemisinin, instead of focusing on the mode of interaction between artemisinin and heme or hemozoin. This suggests that artemisinin and its endoperoxides derivatives likely hit the Achilles’ heel of hemozoin-producing and iron-dependent organisms.

A self-purifying microfluidic system for identifying drugs acting against adult schistosomes

“…PZQ triggers a sudden calcium efflux that paralyses worms and thus has an immediate effect on worm attachment capability. By contrast, the mode of action of ART is more pleiotropic with the production of free radicals that requires the presence of heme in the worm gut, a by-product of haemoglobin degradation [59]. The production of free radicals induces both oxidative and metabolic stresses and results in damage to tegument, tissues and reproductive organs [60,61].…”

What exactly does the PfK13 mutation in Plasmodium falciparum change?

“…Sediments were dissolved in 250 µL of 2.5% SDS buffer and 20 µL of 2.5 mol/L NaOH. The absorbance of hemozoin at 400 nm was measured using Nanodrop 2000 to quantify its content [25].…”

“…Hemozoin, which is beginning to be considered as the vector of HI in hemozoin-forming organisms, functions their reproduction [25,27]. The change in hemozoin content is correlated with the utilization of HI and artemisinin sensitivity [16].…”

Recent Advances in Anti-Schistosomiasis Drug Discovery

“…Inhibiting the parasites' heme polymerization, then, presents another anti-schistosomiasis strategy; this is considered to be the antischistosomal mode of action for several antimalarials [113,114]. However, recent work showing that some hemozoin in the Schistosoma gut is actually consumed to yield free iron for egg development indicates that there is more to learn about hemozoin formation in this parasite [115].…”