IL-1 protects from fatal candidiasis by inhibiting oxidative phosphorylation and hypoxia
Systemic candidiasis is a life-threatening infectious disease. A recent study by Horn et al. in the Kopf lab at ETH Zurich reveals different mechanisms by which the multi-functional cytokine IL-1 protects from Candida albicans overgrowth in the kidney and brain.
Candida albicans is a commensal fungal organism commonly found in the intestinal microbiota of most humans. However, it can also act as an opportunistic pathogen. Systemic candidiasis occurs in immunocompromised individuals or hospitalized patients when Candida enters the bloodstream and invades internal organs such as the kidneys and brain, resulting in a very high mortality rate.
By studying several conditional IL-1R knockout mouse strains, the data revealed how the multifunctional cytokine IL-1 protects against candidiasis in the brain and kidneys and, thereby, mortality. IL-1R signaling in an as-yet unidentified non-immune cell mediates protection by facilitating the rapid migration of innate immune cells to the infected brain, while the protective mechanism in the kidneys differs. IL-1R-deficiency across all cell types in the kidney, but immune cells, revealed excessive metabolic activity and oxidative phosphorylation within a few hours upon infection, causing localized hypoxia at infection foci. By showing that hypoxia promotes fungal growth and pathogenicity, the data demonstrate that IL-1R-signaling in non-immune cells is required to prevent fatal candidiasis by facilitating neutrophil and monocyte migration to the brain and by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia in the kidney.
Link to the paper in external page "Nature Communications".