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 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.

• Authors: Michael Riedelberger, Philipp Penninger, Michael Tscherner, Markus Seifert, Sabrina Jenull, Carina Brunnhofer, Bernhard Scheidl, Irina Tsymala, Christelle Bourgeois, Andriy Petryshyn, Walter Glaser, Andreas Limbeck, Birgit Strobl, Guenter Weiss, Karl Kuchler
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 27 Issue 3 Pg. 454-466.e8 (Mar 11 2020) ISSN: 1934-6069 [Electronic] United States
• PMID: 32075740 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Bach1 protein, mouse
• Basic-Leucine Zipper Transcription Factors
• Cation Transport Proteins
• Interferon Type I
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• metal transporting protein 1
• Iron
• Jak1 protein, mouse
• Janus Kinase 1

Topics

• Adult
• Animals
• Basic-Leucine Zipper Transcription Factors (immunology)
• Candida glabrata (pathogenicity)
• Candidiasis (immunology)
• Cation Transport Proteins (immunology)
• Cells, Cultured
• Female
• Homeostasis
• Humans
• Immune Evasion
• Interferon Type I (immunology)
• Iron (physiology)
• Janus Kinase 1 (immunology)
• Macrophages (immunology, microbiology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (immunology)
• Phagosomes (microbiology)
• Spleen (immunology)