Iron, copper and zinc isotope ratios in malaria infection reveal signatures of the Plasmodium biology and host mice response to the infection.

The metallome of asexual blood stages in Plasmodium berghei-infected mice was examined via Fe, Cu and Zn concentrations and isotope ratios. Isotopic compositions of Fe, Cu and Zn underwent alterations in parasitized red blood cells, suggesting that parasites are highly capable in acquiring and metabolizing essential metals from the host. A hepatic Fe-overload was accompanied by a depletion in the heavier Fe isotopes, indicating a mouse response to compensate for anemia by promptly mobilizing isotopically heavier Fe stores. A discrete hepatic Cu deficiency, but significantly lighter Cu isotopic composition in the liver were observed, alongside a release of Cu into the bloodstream through ceruloplasmin, indicating a contribution of Cu in potentiating Fe release from hepatic stores. The hepatic Zn concentration did not change, while a lighter Zn isotopic composition in both parasites and livers was observed. Our findings argue for a central role of Fe and an auxiliary role of Cu within malaria anemia, while Zn seems to respond to a host immunity component. This novel approach of including high-precision isotopic analysis to study the metallomics can be useful for dissecting a long-standing gap in the knowledge of metal homeostasis in host-microbe interactions and organ-specific changes in host mammalians.