Document Type
Article
Publication Date
2019
Digital Object Identifier (DOI)
https://doi.org/10.26508/lsa.201800292
Abstract
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.
Rights Information
This work is licensed under a Creative Commons Attribution 4.0 License.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Life Science Alliance, v. 2, issue 2, art. e201800292
Scholar Commons Citation
Cockburn, Chelsea L.; Green, Ryan S.; Damle, Sheela R.; Martin, Rebecca K.; Ghahrai, Naomi N.; Colonne, Punsiri M.; Fullerton, Marissa S.; Conrad, Daniel H.; Chalfant, Charles E.; Voth, Daniel E.; Rucks, Elizabeth A.; Gilk, Stacey D.; and Carlyon, Jason A., "Functional Inhibition of Acid Sphingomyelinase Disrupts Infection by Intracellular Bacterial Pathogens" (2019). Molecular Biosciences Faculty Publications. 64.
https://digitalcommons.usf.edu/bcm_facpub/64
