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| - Metallomic Analysis of Macrophages Infected with Histoplasma capsulatum Reveals a Fundamental Role for Zinc in Host Defenses
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| - The fungal pathogen Histoplasma capsulatum evades the innate and adaptive immune responses and thrives within resting macrophages. Cytokines that induce antimicrobial activity, such as granulocyte macrophage colony-stimulating factor (GM-CSF), inhibit H. capsulatum growth in macrophages. Conversely, interleukin 4 inhibits the killing of intracellular pathogens. Using inductively coupled plasma mass spectrometry, we examined alterations in the metal homeostasis of murine H. capsulatum-infected macrophages that were exposed to activating cytokines. Decreases in the levels of iron (Fe2+ and Fe3+) and zinc (Zn2+) were observed in infected, GM-CSF-treated macrophages compared with those in infected controls. Interleukin 4 reversed the antifungal activity of GM-CSF-activated macrophages and was associated with increased intracellular Zn2+ levels. Chelation of Zn2+ inhibited yeast replication in both the absence of macrophages and the presence of macrophages. Treatment of cells with GM-CSF altered the host Zn2+ binding species profile. These results establish that Zn2+ deprivation may be a host defense mechanism utilized by macrophages.
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