Mosquito metallomics reveal copper and iron as critical factors for Plasmodium infection

Iron and copper chelation restricts Plasmodium growth in vitro and in mammalian hosts. The parasite alters metal homeostasis in red blood cells to its favor, for example metabolizing hemoglobin to hemozoin. Metal interactions with the mosquito have not, however, been studied. Here, we describe the metallomes of Anopheles albimanus and Aedes aegypti throughout their life cycle and following a blood meal. Consistent with previous reports, we found evidence of maternal iron deposition in embryos of Ae. aegypti, but less so in An. albimanus. Sodium, potassium, iron, and copper are present at higher concentrations during larval developmental stages. Two An. albimanus phenotypes that differ in their susceptibility to Plasmodium berghei infection were studied. The susceptible white stripe (ws) phenotype was named after a dorsal white stripe apparent during larval stages 3, 4, and pupae. During larval stage 3, ws larvae accumulate more iron and copper than the resistant brown stripe (bs) phenotype counterparts. A similar increase in copper and iron accumulation was also observed in the susceptible ws, but not in the resistant bs phenotype following P. berghei infection. Feeding ws mosquitoes with extracellular iron and copper chelators before and after receiving Plasmodium-infected blood protected from infection and simultaneously affected follicular development in the case of iron chelation. Unexpectedly, the application of the iron chelator to the bs strain reverted resistance to infection. Besides a drop in iron, iron-chelated bs mosquitoes experienced a concomitant loss of copper. Thus, the effect of metal chelation on P. berghei infectivity was strain-specific.
Author summary To establish a life cycle between insect and mammalian hosts, the malaria parasite has evolved mechanisms to manage metal ions from the distinct microenvironments it encounters. Previous work has addressed how interference using metal chelation affects parasite development in human, primate, and rodent hosts. Similar studies in mosquito species that harbor Plasmodium have not been performed. Here, we address such micronutrient relationships in three steps. First, we characterized how the metallome fluctuates during development in two species of mosquito. Second, we asked whether susceptibility to Plasmodium infection correlated with a differential response in mosquito metal homeostasis. Third, we tested the effects of iron and copper chelation treatment of adult mosquitoes concerning propensity of infection and mosquito reproduction. Metal ions offer a promising target in the ongoing efforts to control the mosquito-borne disease.