Lohia Gaurav Kumar, Shah Awantika, Balaji Kithiganahalli Narayanaswamy
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka 560012, India.
iScience. 2025 Aug 20;28(9):113405. doi: 10.1016/j.isci.2025.113405. eCollection 2025 Sep 19.
An opportunistic fungal pathogen, , 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 infection. 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 pathogenesis.
一种机会性真菌病原体，可导致隐球菌性脑膜炎，并且在免疫功能低下的个体中常常与高死亡率相关。代谢改变的富含脂质的泡沫巨噬细胞的形成是各种细胞内病原体用来在宿主体内获取营养源和生态位的一种成功策略。在此，我们阐明了巨自噬，特别是脂噬，在感染期间脂质失调中的作用。由驱动的WNT信号激活在组蛋白修饰剂赖氨酸特异性去甲基化酶1（LSD1）的调节作用下导致宿主巨噬细胞中异常脂质积累。在肺部感染的小鼠模型中，靶向宿主LSD1导致肺部真菌负荷显著降低，同时肺部病理状况改善且肺内脂质含量减少。该研究突出了宿主表观遗传调控在发病机制中通过调节脂噬来调控泡沫巨噬细胞形成的重要性。
