Responses to Nutritional Immunity Imposed by Macrophage Activation.

The fungal pathogen resides within the phagosome of host phagocytic cells. Within this intracellular compartment, 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, 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 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 yeasts. In response, 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 replication with the onset of adaptive immunity.