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

研究成果: Article同行評審

24 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)689-702
頁數14
期刊American Journal of Respiratory Cell and Molecular Biology
53
發行號5
DOIs
出版狀態Published - 2015 十一月

All Science Journal Classification (ASJC) codes

  • 分子生物學
  • 肺和呼吸系統醫學
  • 臨床生物化學
  • 細胞生物學

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