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

• Published in: American journal of respiratory cell and molecular biology Vol. 53; no. 5; pp. 689 - 702
• Main Authors: Statt, Sarah, Ruan, Jhen-Wei, Hung, Li-Yin, Chang, Ching-Yun, Huang, Chih-Ting, Lim, Jae Hyang, Li, Jian-Dong, Wu, Reen, Kao, Cheng-Yuan
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.11.2015
• Subjects: Animals; Bacterial infections; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - toxicity; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - toxicity; Bacteriology; Cell Line, Transformed; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - pathology; Hemolysin Proteins - antagonists & inhibitors; Hemolysin Proteins - toxicity; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - immunology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Immunity, Innate - drug effects; Injections, Intraperitoneal; Kinases; Lung - drug effects; Lung - immunology; Lung - pathology; Mice; Mice, Inbred C57BL; Mortality; Original Research; Pravastatin - immunology; Pravastatin - pharmacology; Primary Cell Culture; Respiratory Mucosa - drug effects; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Simvastatin - immunology; Simvastatin - pharmacology; Staphylococcus aureus - chemistry; Streptococcus pneumoniae - chemistry; Streptolysins - antagonists & inhibitors; Streptolysins - toxicity; Studies; Toxins; simvastatin; cholesterol; pneumolysin; pneumonia; airway epithelium
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2014-0391OC

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.