metallothionein and Histoplasmosis

Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7; the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H⁺ channel function and triggered reactive oxygen species generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.

Topics: Animals; Cation Transport Proteins; Gene Expression Regulation; Golgi Apparatus; Granulocyte-Macrophage Colony-Stimulating Factor; Histoplasma; Histoplasmosis; Host-Pathogen Interactions; Humans; Macrophage Activation; Macrophages, Peritoneal; Metallothionein; Mice; Mice, Transgenic; NADPH Oxidases; Phagosomes; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Superoxides; Zinc