Exploring how antibiotics impair antifungal immunity

Bojang, Ebrima (2024). Exploring how antibiotics impair antifungal immunity. University of Birmingham. Ph.D.

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Abstract

Prolonged antibiotic use is a controllable risk factor for systemic candidiasis. In recent years, antibiotics have been shown to have off-target detrimental effects on immune cells, but whether antibiotics disrupt antifungal immunity is unknown. Drummond and colleagues recently found that the antibiotic vancomycin enhanced mortality from invasive candidiasis in mice, whereas other antibiotics (e.g., metronidazole) did not affect susceptibility. To examine the mechanisms by which vancomycin impairs anti-Candida immunity, I explored how vancomycin pre-treatment of bone-marrow derived macrophages (BMDMs) impacted their responses to C. albicans challenge. Vancomycin-treated macrophages had reduced fungal killing, although phagocytosis of yeast cells was unaffected. Instead, vancomycin causes macrophage mitochondrial dysfunction which is accompanied with increased reactive oxygen species (ROS) production. ROS seemingly contributes to early inflammasome priming thus accelerating inflammasome activation and pyroptosis during C. albicans infections. Early inflammasome activation and pyroptosis potentially causes macrophages to have reduced time to exert all their antifungal properties on C. albicans thus causing reduced killing. Taken together, these results improve our understanding of the pathways regulating antifungal immunity in macrophages and suggest that antibiotic-induced susceptibility to C. albicans may be partly driven by disrupted macrophage function.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):