title: Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses.
abstract: 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 (Fe(2+) and Fe(3+)) and zinc (Zn(2+)) 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 Zn(2+) levels. Chelation of Zn(2+) inhibited yeast replication in both the absence of macrophages and the presence of macrophages. Treatment of cells with GM-CSF altered the host Zn(2+) binding species profile. These results establish that Zn(2+) deprivation may be a host defense mechanism utilized by macrophages.
authors: Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0560, USA. winterms@ucmail.uc.edu
authors: Michael S
authors: MS
authors: Winters
authors: Qilin
authors: Q
authors: Chan
authors: Joseph A
authors: JA
authors: Caruso
authors: George S
authors: GS
authors: Deepe
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D006658:Histoplasma / Q000276:immunology*; D007501:Iron / Q000032:analysis / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000737:chemistry* / Q000276:immunology* / Q000382:microbiology; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D015032:Zinc / Q000032:analysis* / Q000276:immunology*
chemical_list: D002614:Chelating Agents; D016207:Cytokines; D007501:Iron; D015032:Zinc