Histone demethylase LSD1 regulates lipid homeostasis during Cryptococcus neoformans infection

An opportunistic fungal pathogen, Cryptococcus neoformans (C. neoformans) , causes cryptococcal meningitis and is frequently associated with high mortality in immunocompromised individuals, particularly in HIV patients. Formation of metabolically altered lipid-rich foamy macrophages has been reported as a successful strategy employed 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. Our study highlights a pivotal role of lipophagy during infection, showing that 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 amelioration of lung pathology and reduction of 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.