TY - JOUR T1 - Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800292 VL - 2 IS - 2 SP - e201800292 AU - Chelsea L Cockburn AU - Ryan S Green AU - Sheela R Damle AU - Rebecca K Martin AU - Naomi N Ghahrai AU - Punsiri M Colonne AU - Marissa S Fullerton AU - Daniel H Conrad AU - Charles E Chalfant AU - Daniel E Voth AU - Elizabeth A Rucks AU - Stacey D Gilk AU - Jason A Carlyon Y1 - 2019/04/01 UR - https://www.life-science-alliance.org/content/2/2/e201800292.abstract N2 - 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—Anaplasma phagocytophilum, Coxiella burnetii, Chlamydia trachomatis, and Chlamydia pneumoniae. Vacuole maturation, replication, and infectious progeny generation by A. phagocytophilum, which exclusively hijacks LDL cholesterol, are halted and C. burnetii, 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 A. phagocytophilum or C. burnetii. A. phagocytophilum 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. ER -