Type I Interferon Response Dysregulates Host Iron Homeostasis and Enhances Candida glabrata Infection

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 pro-mote the dysregulation of iron homeostasis in mac-rophages during systemic infections with the intra-cellular pathogen Candida glabrata, leading to fungal survival and persistence. By engaging JAK1, IFNs-I disturb the balance of the transcriptional acti-vator NRF2 and repressor BACH1 to induce downre-gulation of the key iron exporter Fpn1 in macro-phages. 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, facili-tating fungal intracellular replication and immune evasion. Thus, IFNs-I are central regulators of iron homeostasis, which can impact infection, and re-stricting iron bioavailability may offer therapeutic strategies to combat invasive fungal infections.