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The fungal pathogen  Histoplasma capsulatum  resides within the phagosome of host phagocytic cells. Within this intracellular compartment,  Histoplasma  yeast replication requires the acquisition of several essential nutrients, including metal ions. Recent work has shown that while iron, zinc, and copper are sufficiently abundant in resting macrophages, cytokine activation of these host cells causes restriction of these metals from intracellular yeasts as a form of nutritional immunity. Faced with limited iron availability in the phagosome following macrophage activation by IFN-γ,  Histoplasma  yeasts secrete iron-scavenging siderophores and employ multiple strategies for reduction of ferric iron to the more physiologically useful ferrous form. IFN-γ activation of macrophages also limits availability of copper in the phagosome, forcing  Histoplasma  reliance on the high affinity Ctr3 copper importer for copper acquisition. GM-CSF activation stimulates macrophage production of zinc-chelating metallothioneins and zinc transporters to sequester zinc from  Histoplasma  yeasts. In response,  Histoplasma  yeasts express the Zrt2 zinc importer. These findings highlight the dynamics of phagosomal metal ion concentrations in host-pathogen interactions and explain one mechanism by which macrophages become a less permissive environment for  Histoplasma  replication with the onset of adaptive immunity.

Histoplasma Responses to Nutritional Immunity Imposed by Macrophage Activation