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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\u20131,000 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, \u03b1-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\u2013dependent, 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.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0391oc","type":"journal-article","created":{"date-parts":[[2015,4,15]],"date-time":"2015-04-15T11:56:35Z","timestamp":1429098995000},"page":"689-702","source":"Crossref","is-referenced-by-count":37,"title":["Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells"],"prefix":"10.1093","volume":"53","author":[{"given":"Sarah","family":"Statt","sequence":"first","affiliation":[{"name":"Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jhen-Wei","family":"Ruan","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 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