Infectious diseases remain a leading cause of morbidity and mortality worldwide. Antibiotics are used to treat many common forms of bacterial infections. However, the discovery of new classes of antibiotics has lagged behind in the last several decades, and yet the emergence of multi-drug resistant bacterial strains due to the widespread overuse of antibiotics is a growing problem. There is a critical need for antibacterial agents not subject to currently observed resistance mechanisms. Pneumonia kills approximately two million children each year worldwide and millions of people get pneumonia annually in the United States alone. Airway epithelia are the initial and primary sites of many bacterial contacts and their barrier and immunity functions are critical to fight infections. Using primary normal human bronchial epithelial (NHBE) cells and an immortalized normal bronchial epithelial cell line, HBE1, here we show that the prior exposure to statins confers significant cellular resistance to the cytotoxicity of pneumolysin and -hemolysin. Pneumolysin and -hemolysin are the main pore-forming toxins, the single largest class of bacterial virulence factors, shown to play critical roles in bacterial pathogenesis respectively in Streptococcus and , two common causes of bacterial infections. We further found that the protection requires protein pneumoniae Staphylococcus aureus synthesis and is calcium dependent. With siRNA gene silencing, pharmacological inhibitors, immuno fluorescence microscopy and biochemical approaches, we have delineated the statin-mediated cellular protection mechanisms in airway epithelial cells. Our animal experiment results further suggest that statin pre-treatment could reduce the lung inflammation caused by pneumolysin. The ultimate goal of this study is to elucidate the interactions of pore-forming toxins and the host cells at the molecular level and this might be potentially developed as a novel host-directed adjuvant therapy in pore-forming toxin-related bacterial infections.
Date:
2013-05-19
Relation:
American Journal of Respiratory and Critical Care Medicine. 2013 May 19;187:Meeting Abstract A6095.
