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Published on: November 27, 2014
IL-1 protects from fatal systemic candidiasis in mice by inhibiting oxidative phosphorylation and hypoxia
Sofia Horn1, Mareike Schmid1, Ivan Berest1
1Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Abstract:
Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.
Insights
Interleukin-1 receptor (IL-1R) signaling in non-hematopoietic cells is vital for controlling invasive Candida albicans infections. This pathway prevents excessive metabolic activity and hypoxia, crucial for survival against candidiasis.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Invasive Candida albicans infections are life-threatening, with high mortality rates.
- The role of Interleukin-1 (IL-1) in combating C. albicans is known, but its precise mechanisms are not fully understood.
Purpose of the Study:
- To elucidate the cellular mechanisms by which IL-1R signaling mediates protection against invasive candidiasis.
- To investigate the specific cell types and tissues where IL-1R signaling is critical for host defense.
Main Methods:
- Utilized global and conditional Il1r1 knockout mouse models.
- Employed single-nucleus RNA sequencing (snRNA-seq) to analyze cellular responses.
- Assessed fungal clearance, immune cell recruitment, and metabolic changes in infected tissues (kidney and brain).
Main Results:
- IL-1R signaling in non-hematopoietic cells, particularly in the kidney endothelium, is essential for fungal clearance, independent of neutrophil recruitment.
- In the brain, IL-1R signaling indirectly recruits immune cells by modulating chemokines and adhesion molecules.
- Il1r1 deficiency leads to rapid metabolic reprogramming, characterized by excessive oxidative phosphorylation and localized hypoxia in kidney tissues, which promotes fungal growth and pathogenicity.
Conclusions:
- IL-1R signaling in non-hematopoietic cells is indispensable for preventing fatal invasive candidiasis.
- This signaling pathway acts by suppressing detrimental metabolic shifts, including excessive oxidative phosphorylation and hypoxia, at infection sites.
