1. Type I Interferon Response Dysregulates Host Iron Homeostasis and Enhances Candida glabrata Infection.
- Author
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Riedelberger, Michael, Penninger, Philipp, Tscherner, Michael, Seifert, Markus, Jenull, Sabrina, Brunnhofer, Carina, Scheidl, Bernhard, Tsymala, Irina, Bourgeois, Christelle, Petryshyn, Andriy, Glaser, Walter, Limbeck, Andreas, Strobl, Birgit, Weiss, Guenter, and Kuchler, Karl
- Abstract
Type I interferons (IFNs-I) fulfil multiple protective functions during pathogenic infections, but they can also cause detrimental effects and enhance immunopathology. Here, we report that IFNs-I promote the dysregulation of iron homeostasis in macrophages during systemic infections with the intracellular pathogen Candida glabrata , leading to fungal survival and persistence. By engaging JAK1, IFNs-I disturb the balance of the transcriptional activator NRF2 and repressor BACH1 to induce downregulation of the key iron exporter Fpn1 in macrophages. This leads to enhanced iron accumulation in the phagolysosome and failure to restrict fungal access to iron pools. As a result, C. glabrata acquires iron via the Sit1/Ftr1 iron transporter system, facilitating fungal intracellular replication and immune evasion. Thus, IFNs-I are central regulators of iron homeostasis, which can impact infection, and restricting iron bioavailability may offer therapeutic strategies to combat invasive fungal infections. • IFN-I-dependent surveillance ofcandidiasis dysregulates host iron homeostasis • IFNs-I disturb iron metabolism in macrophages via the NRF2 control axis • IFN-I-triggered iron accumulation in phagosomes enhances pathogen fitness • Ablation of fungal iron uptake transporters abrogates fungal fitness in vivo During invasive infections, macrophages and fungal pathogens compete for essential nutrients such as iron. Riedelberger et al. show that IFN-I immune responses are detrimental during systemic Candida glabrata infections, owing to a dysregulated control of host iron homeostasis, which in turn promotes fungal fitness and immune evasion. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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