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 - Funding Information:
We thank Joao F Pedra (University of Maryland, Baltimore, MD), Robert A Heinzen (NIAID, Hamilton, MT), and Ted Hackstadt (NIAID, Hamilton, MT) for critical review of this manuscript. We thank Waheeda A Naimi for technical assistance. Confocal micrographs of A. phagocytophilum–infected cells were obtained at the VCU Microscopy Facility, which is supported, in part, with funding from National Institutes of Health - National Institute of Neurological Disorders and Stroke (NIH-NINDS) Center core grant 5P30NS047463 and NIH-NCI Cancer Center Support Grant (P30 CA016059). Chlamydial images were acquired with the assistance of Janice A Taylor and James R Talaska in the University of Nebraska Medical Center Advanced Microscopy Core Facility, which is funded by the Fred and Pamela Buffet Cancer Center Support Grant (P30CA036727) and an Institutional Development Award from National Institute of General Medical Sciences (NIGMS) of the NIH (P30GM106397). JA Carlyon is supported by National Institutes of Health - National Institute of Allergy and Infectious Diseases (NIH-NIAID) grants 1R01 AI139072 and 2R01 AI072683. CE Chalfant is supported by NIH-NIAID grant 1R01 AI139072. DH Conrad is supported by NIH-NIAID grant 5R01 AI018697. DE Voth is supported by NIH-NIAID grant 1R21 AI127931 and NIH/NIGMS grant 1P20 GM103625. EA Rucks is supported by 1R01 AI114670 and University of Nebraska Medical Center (UNMC) start-up funds. SD Gilk is supported by NIH-NIAID grants R21AI121786 and R01AI139176.
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 -