Abstract
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 glabrata can 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 both in vitro and in vivo during 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.
Highlights
Candida glabrata represents an opportunistic intracellular human fungal pathogen, causing life-threatening infections in immunocompromised patients (Pappas et al, 2018)
Zinc-loading is inhibited by IFNsI, 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)
IFNs-I Dysregulate Zn Homeostasis Genes in the Spleen during Systemic C. glabrata (Cg) Infections We have previously reported that IFNs-I are detrimental for the host during systemic Cg infections (Bourgeois et al, 2011)
Summary
Candida glabrata represents an opportunistic intracellular human fungal pathogen, causing life-threatening infections in immunocompromised patients (Pappas et al, 2018). Adaptive evolution equipped this fungal pathogen with a vast repertoire of defense mechanisms that facilitate immune evasion (Kasper et al, 2015; Kumar et al, 2019). The immune defense in turn mounts local and systemic pro-inflammatory responses to boost clearing of Cg by macrophages and neutrophils (Netea et al, 2015). IFNs-I set pro-inflammatory stimuli aimed at supporting immune surveillance and defense. Pro-inflammatory IFN-I actions can be both beneficial and detrimental in infectious settings, in cases where excessive immunopathology drives self-imposed ‘‘collateral’’ oxidative damage to host tissues (Majer et al, 2012; McNab et al, 2015). We have previously reported that IFNs-I drive the persistence of Cg in brain, liver, and spleen of Ifnar1À/À mice, thereby dysregulating the cellular iron homeostasis in macrophage subsets, which inadvertently facilitates fungal iron acquisition that enhances fungal fitness (Bourgeois et al, 2011; Riedelberger et al, 2020)
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