Leishmania secretory factor GP63 targets the DICER1/miR-122/hepcidin axis in host macrophages to deplete Nramp1

Micronutrient sequestration is a powerful host defense against intracellular pathogens. A key player in this is Nramp1, which effluxes iron from phagolysosomes, depriving the engulfed pathogens of this essential element. Leishmania counters this by triggering hepcidin-mediated proteasomal degradation of Nramp1. Interestingly, Leishmania major conditioned media induced hepcidin expression and Nramp1 degradation even in uninfected macrophages, resulting in enhanced endo/lysosomal iron. This observation led to the identification of the secretory factor GP63 responsible for Nramp1 degradation. Conditioned media from the LmGP63 ^−/- strain failed to upregulate hepcidin or degrade Nramp1. Further, GP63 was found to deplete macrophage DICER1, impairing maturation of miR-122, a negative regulator of hepcidin. Consistent with in vitro results, the LmGP63 ^−/- strain, unlike its wild type counterpart, was unable to deplete DICER1, induce hepcidin expression or suppress Nramp1 in infected mice. Collectively, we uncover a novel role for Leishmania GP63 in targeting the host DICER1/miR-122 axis to trigger hepcidin expression and Nramp1 degradation, facilitating iron acquisition by the parasite.