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Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens

Chelsea L Cockburn1, Ryan S Green1, Sheela R Damle1

  • 1Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, USA.

Life Science Alliance
|March 24, 2019
PubMed

Insights

Acid sphingomyelinase (ASM) is crucial for vacuole-adapted bacteria that hijack cholesterol. Inhibiting ASM halts bacterial infection cycles, offering potential therapies for diseases caused by these intracellular pathogens.

Area of Science:

  • Microbiology
  • Cell Biology
  • Biochemistry

Background:

  • Intracellular bacteria residing in host cell vacuoles cause significant human diseases.
  • Many vacuole-adapted bacteria rely on low-density lipoprotein (LDL) cholesterol for survival and replication.
  • Acid sphingomyelinase (ASM) plays a role in regulating LDL cholesterol within lysosomes.

Purpose of the Study:

  • To investigate the role of ASM activity in the infection cycles of key vacuole-adapted intracellular bacteria.
  • To evaluate the efficacy of functional inhibitors of ASM (FIASMAs) as a potential therapeutic strategy.

Main Methods:

  • Utilized functional inhibitors of ASM (FIASMAs) to block ASM activity in host cells.
  • Infected host cells and mice with various intracellular bacteria, including *Anaplasma phagocytophilum*, *Coxiella burnetii*, *Chlamydia trachomatis*, and *Chlamydia pneumoniae*.
  • Assessed the impact of FIASMAs on bacterial vacuole maturation, replication, and infectious progeny generation.

Main Results:

  • ASM activity was essential for the infection cycles of all tested vacuole-adapted bacteria.
  • FIASMAs completely halted *Anaplasma phagocytophilum* infection by blocking LDL cholesterol hijacking.
  • *Coxiella burnetii* was killed by FIASMAs due to lysosomal cholesterol accumulation.
  • Chlamydiae infections were suppressed by FIASMAs, though less effectively than *A. phagocytophilum* or *C. burnetii*.
  • *A. phagocytophilum* failed to productively infect ASM-deficient or FIASMA-treated mice.

Conclusions:

  • ASM is a critical host factor for intracellular bacterial pathogens that manipulate cholesterol trafficking.
  • FIASMAs demonstrate significant potential as host-directed therapies against diseases caused by these bacteria.
  • Targeting ASM offers a novel therapeutic avenue for treating infections by LDL cholesterol-dependent intracellular bacteria.

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