Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, USA.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Life Sci Alliance. 2019 Mar 22;2(2). doi: 10.26508/lsa.201800292. Print 2019 Apr.
Intracellular bacteria that live in host cell-derived vacuoles are significant causes of human disease. Parasitism of low-density lipoprotein (LDL) cholesterol is essential for many vacuole-adapted bacteria. Acid sphingomyelinase (ASM) influences LDL cholesterol egress from the lysosome. Using functional inhibitors of ASM (FIASMAs), we show that ASM activity is key for infection cycles of vacuole-adapted bacteria that target cholesterol trafficking-, , , and Vacuole maturation, replication, and infectious progeny generation by , which exclusively hijacks LDL cholesterol, are halted and , for which lysosomal cholesterol accumulation is bactericidal, is killed by FIASMAs. Infection cycles of Chlamydiae, which hijack LDL cholesterol and other lipid sources, are suppressed but less so than or fails to productively infect ASM or FIASMA-treated mice. These findings establish the importance of ASM for infection by intracellular bacteria and identify FIASMAs as potential host-directed therapies for diseases caused by pathogens that manipulate LDL cholesterol.
生活在宿主细胞来源的空泡中的细胞内细菌是人类疾病的重要原因。许多适应空泡的细菌都需要寄生低密度脂蛋白（LDL）胆固醇。酸性鞘磷脂酶（ASM）影响溶酶体中 LDL 胆固醇的排出。我们使用 ASM 的功能抑制剂（FIASMAs）表明，ASM 活性对于靶向胆固醇运输的空泡适应细菌的感染周期至关重要， ， ，和 空泡成熟、复制和感染性后代的产生， 专门劫持 LDL 胆固醇，被阻止，而对于溶酶体胆固醇积累具有杀菌作用的 ，则被 FIASMAs 杀死。劫持 LDL 胆固醇和其他脂质来源的衣原体的感染周期被抑制，但不如 或 那样有效， 不能有效地感染 ASM 或 FIASMA 处理的小鼠。这些发现确立了 ASM 对于细胞内细菌感染的重要性，并将 FIASMAs 确定为潜在的宿主定向治疗方法，用于治疗操纵 LDL 胆固醇的病原体引起的疾病。
