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Alliance"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>Intracellular bacteria that live in host cell\u2013derived 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\u2014<jats:italic>Anaplasma phagocytophilum<\/jats:italic>,<jats:italic>Coxiella burnetii<\/jats:italic>,<jats:italic>Chlamydia trachomatis<\/jats:italic>, and<jats:italic>Chlamydia pneumoniae.<\/jats:italic>Vacuole maturation, replication, and infectious progeny generation by<jats:italic>A. phagocytophilum<\/jats:italic>, which exclusively hijacks LDL cholesterol, are halted and<jats:italic>C. burnetii<\/jats:italic>, 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<jats:italic>A. phagocytophilum<\/jats:italic>or<jats:italic>C. burnetii<\/jats:italic>.<jats:italic>A. phagocytophilum<\/jats:italic>fails to productively infect ASM<jats:sup>\u2212\/\u2212<\/jats:sup>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.<\/jats:p>","DOI":"10.26508\/lsa.201800292","type":"journal-article","created":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T20:15:14Z","timestamp":1553285714000},"page":"e201800292","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens"],"prefix":"10.26508","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4423-8614","authenticated-orcid":true,"given":"Chelsea L","family":"Cockburn","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, 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