Iron uptake and virulence in Histoplasma capsulatum

•Iron is required for Hc survival and replication in macrophages.•Loss of the proton pump VMA1 disrupts iron acquisition and virulence both in MΦ and in mice.•Production of siderophores is required for survival in MΦ, and virulence in mice.•The ability to reduce ferric iron to the ferrous is required for Hc survival in MΦ.

Histoplasma capsulatum (Hc) is the causative organism of a spectrum of disease affecting both the immunocompetent and the immunocompromised host. Hc is a dimporhic fungus that converts from conidia to the pathogenic yeast phase after entry into the mammalian host. Despite rapid ingestion by macrophages, it survives intracellularly within the macrophage. The intracellular survival strategy of Hc yeasts focuses on regulating the phagosomal compartment by modulating the intraphagosomal pH to 6.5. As an intracellular pathogen of MΦ, Hc obtains iron from Fe-transferrin, ferritin, or both, via the production of hydroxamate siderophores, and the production of ferric reductases. A better understanding of the mechanisms by which Hc yeasts acquire iron from the host may lead to novel therapeutics for histoplasmosis.