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

17 Citations (Scopus)

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

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Epithelial Cells
Simvastatin
Bacterial Infections
Pravastatin
Mevalonic Acid
Hemolysin Proteins
Gene Silencing
Virulence Factors
Cytotoxicity
Streptococcus pneumoniae
Fluorescence Microscopy
Sepsis
Pneumonia
Microscopic examination
Cardiovascular Diseases
Genes
Cholesterol
Pharmacology
Calcium

Keywords

  • Airway epithelium
  • Cholesterol
  • Pneumolysin
  • Pneumonia
  • Simvastatin

ASJC Scopus subject areas

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

Cite this

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

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 53, No. 5, 01.11.2015, p. 689-702.

Research output: Contribution to journalArticle

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. / Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells. In: American Journal of Respiratory Cell and Molecular Biology. 2015 ; Vol. 53, No. 5. pp. 689-702.
@article{4d06636ca8dc41e2ae666066693ff9a6,
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, 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.",
keywords = "Airway epithelium, Cholesterol, Pneumolysin, Pneumonia, Simvastatin",
author = "Sarah Statt and Ruan, {Jhen Wei} and Hung, {Li Yin} and Chang, {Ching Yun} and Huang, {Chih Ting} and Lim, {Jae Hyang} and Li, {Jian Dong} and Reen Wu and Kao, {Cheng Yuan}",
year = "2015",
month = "11",
day = "1",
doi = "10.1165/rcmb.2014-0391OC",
language = "English (US)",
volume = "53",
pages = "689--702",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

TY - JOUR

T1 - Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells

AU - Statt, Sarah

AU - Ruan, Jhen Wei

AU - Hung, Li Yin

AU - Chang, Ching Yun

AU - Huang, Chih Ting

AU - Lim, Jae Hyang

AU - Li, Jian Dong

AU - Wu, Reen

AU - Kao, Cheng Yuan

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

KW - Airway epithelium

KW - Cholesterol

KW - Pneumolysin

KW - Pneumonia

KW - Simvastatin

UR - http://www.scopus.com/inward/record.url?scp=84930624257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930624257&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2014-0391OC

DO - 10.1165/rcmb.2014-0391OC

M3 - Article

C2 - 25874372

AN - SCOPUS:84930624257

VL - 53

SP - 689

EP - 702

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -