PT  - JOURNAL ARTICLE
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
TI  - Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens
AID  - 10.26508/lsa.201800292
DP  - 2019 Apr 01
TA  - Life Science Alliance
PG  - e201800292
VI  - 2
IP  - 2
4099  - https://www.life-science-alliance.org/content/2/2/e201800292.short
4100  - https://www.life-science-alliance.org/content/2/2/e201800292.full
SO  - Life Sci. Alliance2019 Apr 01; 2
AB  - 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.