title: Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells.
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, α-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.
authors: 1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.
authors: Sarah
authors: S
authors: Statt
authors: 2 Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Jhen-Wei
authors: JW
authors: Ruan
authors: 1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.
authors: Li-Yin
authors: LY
authors: Hung
authors: 1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.
authors: Ching-Yun
authors: CY
authors: Chang
authors: 2 Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Chih-Ting
authors: CT
authors: Huang
authors: 3 Department of Microbiology, Ewha Womans University School of Medicine, Seoul, Korea; and.
authors: Jae Hyang
authors: JH
authors: Lim
authors: 4 Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia.
authors: Jian-Dong
authors: JD
authors: Li
authors: 1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.
authors: Reen
authors: R
authors: Wu
authors: 1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.|2 Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Cheng-Yuan
authors: CY
authors: Kao
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000276:immunology / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017035:Pravastatin / Q000276:immunology / Q000494:pharmacology; D061251:Primary Cell Culture; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019821:Simvastatin / Q000276:immunology / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000737:chemistry; D013296:Streptococcus pneumoniae / Q000737:chemistry; D013301:Streptolysins / Q000037:antagonists & inhibitors* / Q000633:toxicity
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C021091:staphylococcal alpha-toxin; D019821:Simvastatin; D017035:Pravastatin
keywords: airway epithelium; cholesterol; pneumolysin; pneumonia; simvastatin