Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes.

中文翻译：

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囊性纤维化对感染的缺陷反应涉及自噬和脂质代谢。

囊性纤维化（CF）是一种遗传性疾病，有70％的患者发生与苯丙氨酸508缺失有关的蛋白病。CF与多器官功能障碍，慢性炎症和肺部反复感染有关。CF的特征是自噬缺陷，脂质代谢和免疫反应不良。细胞内脂质积聚有利于微生物感染，而自噬不足会损害内在的病原体清除。Myriocin是鞘脂合成的抑制剂，可显着减少炎症，促进肺部微生物清除并诱导自噬和脂质氧化。RNA测序在烟曲霉中进行感染和用霉素治疗的CF患者的单核细胞以及CF支气管上皮细胞系中。在CF单核细胞中也评估了真菌清除率。Myriocin增强CF患者烟曲霉单核细胞的杀伤力。。CF患者的单核细胞和细胞系对感染的反应发生了深刻的转录变化。myriocin调节与炎症，自噬，脂质存储和代谢有关的基因，包括组蛋白和热休克蛋白，其活性与感染的反应有关。我们得出的结论是，鞘脂合成的调控通过促进自噬和脂质消耗来诱导新陈代谢的漂移。这个过程是由转录程序驱动的，该程序可以纠正CF和对照样品之间的部分差异，从而改善CF细胞系和CF外周血单核细胞的感染反应和病原体清除率。