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Life Sci Alliance. 2019 Mar 22;2(2). pii: e201800292. doi: 10.26508/lsa.201800292. Print 2019 Apr.

Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens.

Author information

1
Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, USA.
2
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
3
Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
4
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
5
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
6
Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, USA jason.carlyon@vcuhealth.org.

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.

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