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Published on: November 3, 2014
Histoplasma Responses to Nutritional Immunity Imposed by Macrophage Activation
Peter J Brechting1, Chad A Rappleye2
1Department of Microbiology, Ohio State University, Columbus, OH 43210, USA. brechting.1@osu.edu.
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.
Insights
Host cell activation restricts essential metals like iron, zinc, and copper from the fungal pathogen Histoplasma capsulatum. This nutritional immunity limits pathogen growth by altering metal availability within phagosomes.
Area of Science:
- Medical Mycology
- Immunology
- Host-Pathogen Interactions
Background:
- Histoplasma capsulatum is an intracellular fungal pathogen residing in host phagosomes.
- Pathogen replication depends on acquiring essential nutrients, including metal ions, from the host cell.
Purpose of the Study:
- To investigate how macrophage activation affects the availability of essential metal ions (iron, zinc, copper) for Histoplasma capsulatum.
- To elucidate the mechanisms employed by Histoplasma capsulatum to acquire metals under nutrient-limited conditions.
Main Methods:
- Analysis of metal ion concentrations in phagosomes of resting and activated macrophages.
- Transcriptomic and proteomic analysis of Histoplasma capsulatum in response to metal limitation.
- Functional studies of metal transporters and siderophore production in Histoplasma capsulatum.
Main Results:
- Cytokine activation (IFN-γ, GM-CSF) of macrophages restricts iron, copper, and zinc availability within phagosomes.
- Histoplasma capsulatum employs siderophores and iron reductases to scavenge iron.
- The Ctr3 copper importer and Zrt2 zinc importer are crucial for metal acquisition under nutrient stress.
Conclusions:
- Macrophage activation induces nutritional immunity by limiting metal ion availability to intracellular Histoplasma capsulatum.
- Histoplasma capsulatum has evolved sophisticated strategies to overcome metal starvation, including specific transporters and iron-scavenging molecules.
- Understanding these host-pathogen metal dynamics provides insights into controlling histoplasmosis during adaptive immunity.
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