Beneficial effect of aurothiomalate on murine malaria

Abstract

BackgroundPremature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Aurothiomalate has previously been shown to trigger erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether sodium aurothiomalate influences the intraerythrocytic parasite development in vitro and the clinical course of murine malaria in vivo.MethodsHuman erythrocytes were infected with Plasmodium falciparum BinH in vitro and mice were infected (intraperitoneal injection of 1 × 106 parasitized murine erythrocytes) with Plasmodium berghei ANKA in vivo.ResultsExposure to aurothiomalate significantly decreased the in vitro parasitemia of P. falciparum-infected human erythrocytes without influencing the intraerythrocytic DNA/RNA content. Administration of sodium aurothiomalate in vivo (daily 10 mg/kg b.w. s.c. from the 8th day of infection) enhanced the percentage of phosphatidylserine-exposing infected and noninfected erythrocytes in blood. All nontreated mice died within 30 days of infection. Aurothiomalate-treatment delayed the lethal course of malaria leading to survival of more than 50% of the mice 30 days after infection.ConclusionsSodium aurothiomalate influences the survival of Plasmodium berghei-infected mice, an effect only partially explained by stimulation of eryptosis.

Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery

“…Interestingly, aurothiomalate also reduces Plasmodium parasitemia both in vitro and in infected mice38. However, the mechanism of anti-parasitic action for aurothiomalate could only be partially explained - entailing stimulation of eryptosis in infected RBCs38.…”

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

“…Although elimination of pRBCs has a role in pathogenesis of malarial anemia, contrary to RBC lysis that allows the propagation of merozoites at the end of schizogony, RBC apoptosis could play a beneficial role leading intraerythrocytic-developing parasites to degradation by phagocytosis and consequently reducing parasite burden that directly promotes anemia through RBC lysis. This protective role of erythrocytic apoptosis was previously demonstrated by treating P. berghei -infected mice with the drug aurothiomalate, which triggers apoptosis selectively in pRBCs with no effect on intraerythrocytic parasite development (Alesutan et al, 2010). This in vivo stimulation of pRBC apoptosis delayed the course of parasitemia and mortality of mice, suggesting that the use of drugs to selectively trigger apoptosis pathways in pRBCs could be a strategy to treat malaria in a manner not propitious to generation of parasite resistance, since drugs would target the host cell and not the parasite.…”

Refractoriness of Eryptotic Red Blood Cells to Plasmodium falciparum Infection: A Putative Host Defense Mechanism Limiting Parasitaemia

“…In murine models eryptosis of nRBC was reported during anaemia-associated P. yoelii 17XL infection [8] or during P. berghei ANKA infection when the use of eryptotic inducers was able to enhance eryptosis only in pRBC [26], [27].…”