Iron and Malaria

Abstract

Malaria is one of the most devastating infections found in man and the resurgence of drug resistance has prompted the search for novel chemotherapeutic strategies. Clinical observations have exposed the susceptibility of malaria parasites to iron deficiency, thus the metabolism of iron in parasitized erythrocytes could be a potential antimalarial target. In in vitro experiments, the parasites accumulated approximately four times more non-transferrin-bound iron than diferric transferrin. Both forms were accumulated in a concentration- and time-dependent manner, with more iron being associated with the trophozoite stage than the ring stage. The ferric iron chelating agent, desferrioxamine inhibited the uptake of transferrin and non-transferrin-bound iron in a concentration dependent manner. 2,2’-Bipyridyl, a ferrous iron chelating agent also inhibited the uptake of non-transferrin-bound iron, but did not affect the uptake of diferric transferrin. This indicated that the parasite does not accumulate diferric transferrin by transferrin-receptor mediated endocytosis, but rather by a non-specific endocytotic pathway.

A large quantity of the accumulated iron was associated with the parasite haemozoin. Desferrioxamine effectively reduced the amount of iron associated with the haemozoin, whilst 2,2’-bipyridyl did not, which indicates that the haemozoin-associated iron is in the ferric state. The parasitized erythrocytes were more susceptible to haemolysis by the haemozoin subunits than the uninfected erythrocytes. The presence of chloroquine and 2,2’-bipyridyl potentiated the haemolysis induced by the subunits, whilst desferrioxamine protected the parasitized erythrocytes. The plasma chelating agents and aminocarboxylate compounds were not as effective in inhibiting parasite growth, as desferrithiocin, bathophenanthroline, desferrioxamine and 2,2’-bipyridyl which avidly chelate iron. The additive interaction between the latter two agents and chloroquine, quinine and pyrimethamine, completely eliminated the malaria infection. As did the combination of two lipophilic ferrous or two hydrophilic ferric iron chelating agents, as well as the combination of a hydrophilic ferric and lipophilic ferrous iron chelating agent. Whilst the combination of hydrophilic ferric and hydrophilic ferrous iron chelating agents antagonised each others antimalarial actions. Variables such as inoculum size, extracellular pH, cation supplementation and stage dependency, all affected the antimalarial activity of the iron chelating agents. Thus, the unique pathways involved in the iron metabolism of P. falciparum-infected erythrocytes, could be potential targets for new antimalarial drugs, which are membrane permeable and avidly chelate iron.