Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens

Chelsea L. Cockburn, Ryan S. Green, Sheela R. Damle, Rebecca K. Martin, Naomi N. Ghahrai, Punsiri M. Colonne, Marissa S. Fullerton, Daniel H. Conrad, Charles E. Chalfant, Daniel E. Voth, Elizabeth A Rucks, Stacey D. Gilk, Jason A. Carlyon

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article numbere201800292
JournalLife Science Alliance
Volume2
Issue number2
DOIs
StatePublished - Jan 1 2019

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Sphingomyelin Phosphodiesterase
Anaplasma phagocytophilum
Pathogens
low density lipoprotein cholesterol
Bacterial Infections
LDL Cholesterol
Coxiella burnetii
Vacuoles
pathogen
vacuoles
Bacteria
Acids
pathogens
acids
acid
bacterium
infection
bacteria
disease by pathogen
Chlamydophila pneumoniae

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

Cite this

Cockburn, C. L., Green, R. S., Damle, S. R., Martin, R. K., Ghahrai, N. N., Colonne, P. M., ... Carlyon, J. A. (2019). Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens. Life Science Alliance, 2(2), [e201800292]. https://doi.org/10.26508/lsa.201800292

Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens. / 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.; Carlyon, Jason A.

In: Life Science Alliance, Vol. 2, No. 2, e201800292, 01.01.2019.

Research output: Contribution to journalArticle

Cockburn, CL, Green, RS, Damle, SR, Martin, RK, Ghahrai, NN, Colonne, PM, Fullerton, MS, Conrad, DH, Chalfant, CE, Voth, DE, Rucks, EA, Gilk, SD & Carlyon, JA 2019, 'Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens', Life Science Alliance, vol. 2, no. 2, e201800292. https://doi.org/10.26508/lsa.201800292
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. ; Carlyon, Jason A. / Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens. In: Life Science Alliance. 2019 ; Vol. 2, No. 2.
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