Histoplasma Responses to Nutritional Immunity Imposed by Macrophage Activation.

Peter J Brechting,Chad A Rappleye

doi:10.3390/jof5020045

Peter J Brechting, Chad A Rappleye

Open Access

https://doi.org/10.3390/jof5020045

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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.

Highlights

The fungal pathogen Histoplasma capsulatum causes disease in both immunocompromised and immunocompetent individuals by subverting innate immune defenses of the mammalian host.Histoplasma causes thousands of hospitalizations in the United States and has been estimated to infect 25,000 to 100,000 people annually [1,2]
Treatment with IL-4 during a mouse lung infection increases fungal burden, but this effect was mitigated in Mt3-silenced macrophages [7]. These results demonstrate that increased zinc availability for Histoplasma in M2-differentiated macrophages correlates with increased intracellular proliferation, highlighting the importance of nutritional immunity during infection
Histoplasma yeasts within activated macrophages or macrophages collected from mice after the onset of adaptive immunity showed increased expression of the CTR3 gene further substantiating the cytokine-induced conversion to a copper-limited phagosome [23]

Summary

Introduction

The fungal pathogen Histoplasma capsulatum causes disease in both immunocompromised and immunocompetent individuals by subverting innate immune defenses of the mammalian host. In addition to macrophage strategies designed to actively kill invading microbes, phagocytes can exploit the essentiality of elements and other nutrients by limiting their availability to pathogens. This defense mechanism against pathogenic microbes has been termed “nutritional immunity”. Trace elements present a particular challenge for intracellular Histoplasma yeasts as host macrophages can limit their availability and. The result is a contest between fungal metal acquisition mechanisms and macrophage efforts to restrict such from their intracellular occupants. Macrophage activation is linked to enhanced limitation of trace element availability, thereby illuminating how activated macrophages, unlike resting macrophages, can restrict fungal replication

Acquisition of Zinc

Acquisition of Copper

Acquisition of Iron

Findings

Conclusions