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Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
Published on: September 13, 2024
Histone demethylase LSD1 regulates lipid homeostasis during Cryptococcus neoformans infection
Gaurav Kumar Lohia1, Awantika Shah1, Kithiganahalli Narayanaswamy Balaji1
1Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka 560012, India.
Abstract:
An opportunistic fungal pathogen, Cryptococcus neoformans, causes cryptococcal meningitis and is frequently associated with high mortality in immunocompromised individuals. The formation of metabolically altered lipid-rich foamy macrophages is a successful strategy used by various intracellular pathogens to secure a nutrient source and niche within the host. Herein, we elucidate the involvement of macroautophagy, specifically lipophagy, in lipid dysregulation during C. neoformans infection. C. neoformans driven activation of WNT-signaling leads to an aberrant lipid accumulation in host macrophages under the regulatory role of a histone modifier, Lysine Specific Demethylase 1 (LSD1). In a murine model of pulmonary infection, targeting host LSD1 led to a significant reduction in lung fungal burden, accompanied by improved lung pathology and reduced lipid content in the lungs. The study highlights the significance of host epigenetic regulation in modulating foamy macrophage formation through the regulation of lipophagy during C. neoformans pathogenesis.
Insights
Cryptococcus neoformans infection causes lipid accumulation in macrophages. Targeting the histone modifier LSD1 reduces fungal burden and improves lung pathology by regulating lipophagy.
Area of Science:
- Immunology
- Mycology
- Epigenetics
Background:
- Cryptococcus neoformans is an opportunistic fungal pathogen causing cryptococcal meningitis, with high mortality in immunocompromised individuals.
- Intracellular pathogens utilize lipid-rich foamy macrophages as a nutrient source and niche.
- Lipid dysregulation and foamy macrophage formation are key aspects of C. neoformans pathogenesis.
Purpose of the Study:
- To elucidate the role of macroautophagy, specifically lipophagy, in lipid dysregulation during C. neoformans infection.
- To investigate the involvement of WNT-signaling and the histone modifier Lysine Specific Demethylase 1 (LSD1) in C. neoformans-driven lipid accumulation.
- To evaluate the therapeutic potential of targeting host LSD1 in a murine model of pulmonary infection.
Main Methods:
- Investigated macroautophagy and lipophagy in C. neoformans-infected macrophages.
- Analyzed WNT-signaling pathway activation and LSD1 regulation in host macrophages.
- Utilized a murine model of pulmonary C. neoformans infection to assess the impact of LSD1 targeting.
Main Results:
- C. neoformans infection activates WNT-signaling, leading to aberrant lipid accumulation in macrophages via LSD1.
- Targeting host LSD1 significantly reduced lung fungal burden in a murine model.
- LSD1 inhibition improved lung pathology and decreased lipid content in infected lungs.
Conclusions:
- Host epigenetic regulation by LSD1 plays a critical role in modulating foamy macrophage formation during C. neoformans pathogenesis.
- Lipophagy is significantly involved in lipid dysregulation induced by C. neoformans.
- Targeting host LSD1 represents a potential therapeutic strategy against C. neoformans infection.
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