TY - JOUR
T1 - Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens
AU - Cockburn, Chelsea L.
AU - Green, Ryan S.
AU - Damle, Sheela R.
AU - Martin, Rebecca K.
AU - Ghahrai, Naomi N.
AU - Colonne, Punsiri M.
AU - Fullerton, Marissa S.
AU - Conrad, Daniel H.
AU - Chalfant, Charles E.
AU - Voth, Daniel E.
AU - Rucks, Elizabeth A.
AU - Gilk, Stacey D.
AU - Carlyon, Jason A.
N1 - Publisher Copyright:
2019 Cockburn et al.
PY - 2019
Y1 - 2019
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 2 / 2 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.
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 2 / 2 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.
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U2 - 10.26508/lsa.201800292
DO - 10.26508/lsa.201800292
M3 - Article
C2 - 30902833
AN - SCOPUS:85065736114
SN - 2575-1077
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
IS - 2
M1 - e201800292
ER -