摘要：SummaryHost and fungal pathogens compete for metal ion acquisition during infectious processes, but molecular mechanisms remain largely unknown. Here, we show that type I interferons (IFNs-I) dysregulate zinc homeostasis in macrophages, which employ metallothionein-mediated zinc intoxication of pathogens as fungicidal response. However,Candida glabratacan escape immune surveillance by sequestering zinc into vacuoles. Interestingly, zinc-loading is inhibited by IFNs-I, because a Janus kinase 1 (JAK1)-dependent suppression of zinc homeostasis affects zinc distribution in macrophages as well as generation of reactive oxygen species (ROS). In addition, systemic fungal infections elicit IFN-I responses that suppress splenic zinc homeostasis, thereby altering macrophage zinc pools that otherwise exert fungicidal actions. Thus, IFN-I signaling inadvertently increases fungal fitness bothin vitroandin vivoduring fungal infections. Our data reveal an as yet unrecognized role for zinc intoxication in antifungal immunity and suggest that interfering with host zinc homeostasis may offer therapeutic options to treat invasive fungal infections.Graphical AbstractDisplay OmittedHighlights•Metallothioneins shuttle zinc into macrophage phagosomes to elicit pathogen killing•Zinc sequestration by metallothioneins drives potent fungicidal ROS responses•IFN-I signaling dysregulates host zinc homeostasis during invasive candidiasis•IFNs-I suppress zinc intoxication and promote pathogen fitness and immune evasionImmunology; Immune Respons; Immune Response
