Histoplasma Responses to Nutritional Immunity Imposed by Macrophage Activation

Abstract

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.

Keywords: Histoplasma; copper; immunity; iron; macrophage; phagosome; virulence; zinc.

Figure 1

Metal acquisition mechanisms of intraphagosomal Histoplasma combat metal sequestration by infected macrophages triggered by inflammatory cytokines. In resting macrophages (left panel) iron, zinc, and copper levels are sufficient for Histoplasma growth. Upon activation (right panel), infected macrophages attempt to deprive Histoplasma of essential metals through divalent cation exporters (e.g., Nramp1 and Slc30a7), zinc chelating metallothioneins, and as-yet undefined mechanisms. Under these metal-limited conditions, Histoplasma in turn upregulates the copper and zinc importers, Ctr3 and Zrt2, respectively. Additionally, Histoplasma secretes siderophores to scavenge iron, as well as the Ggt1 protein, which catalyzes a ferric reduction pathway, providing ferrous iron for the yeast.