Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells

Sarah Statt, Jhen Wei Ruan, Li Yin Hung, Ching Yun Chang, Chih Ting Huang, Jae Hyang Lim, Jian Dong Li, Reen Wu, Cheng Yuan Kao

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, a-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.

Original languageEnglish (US)
Pages (from-to)689-702
Number of pages14
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume53
Issue number5
DOIs
StatePublished - Nov 1 2015

Keywords

  • Airway epithelium
  • Cholesterol
  • Pneumolysin
  • Pneumonia
  • Simvastatin

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Medicine(all)

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