RT Journal Article
SR Electronic
T1 Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800292
DO 10.26508/lsa.201800292
VO 2
IS 2
A1 Chelsea L Cockburn
A1 Ryan S Green
A1 Sheela R Damle
A1 Rebecca K Martin
A1 Naomi N Ghahrai
A1 Punsiri M Colonne
A1 Marissa S Fullerton
A1 Daniel H Conrad
A1 Charles E Chalfant
A1 Daniel E Voth
A1 Elizabeth A Rucks
A1 Stacey D Gilk
A1 Jason A Carlyon
YR 2019
UL https://www.life-science-alliance.org/content/2/2/e201800292.abstract
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.