Reactive oxygen species and the MEK/ERK pathway are involved in the toxicity of clostridium perfringens α-toxin, a prototype bacterial phospholipase C.
Clostridium perfringens, the most broadly distributed pathogen in nature, produces a prototype phospholipase C, also called α-toxin, which plays a key role in the pathogenesis of gas gangrene. α-Toxin causes plasma membrane disruption at high concentrations, but the role of intracellular mediators in its toxicity at low concentrations is unknown. This work demonstrates that α-toxin causes oxidative stress and activates the MEK/ERK pathway in cultured cells and furthermore provides compelling evidence that O(2)(-.), hydrogen peroxide, and the OH(.) radical are involved in its cytotoxic and myotoxic effects. The data show that antioxidants and MEK1 inhibitors reduce the cytotoxic and myotoxic effects of α-toxin and demonstrate that edaravone, a clinically used hydroxyl radical trap, reduces the myonecrosis and the mortality caused by an experimental infection with C. perfringens in a murine model of gas gangrene. This knowledge provides new insights for the development of novel therapies to reduce tissue damage during clostridial myonecrosis.
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, 2060 San José, Costa Rica.
Laura
L
Monturiol-Gross
Marietta
M
Flores-Díaz
Cindy
C
Araya-Castillo
María-José
MJ
Pineda-Padilla
Graeme C
GC
Clark
Richard W
RW
Titball
Alberto
A
Alape-Girón
D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives; D001427:Bacterial Toxins / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000633:toxicity*; D002460:Cell Line; D003016:Clostridium perfringens / Q000472:pathogenicity*; D004195:Disease Models, Animal; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000008:administration & dosage; D005738:Gas Gangrene / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology; D017382:Reactive Oxygen Species / Q000633:toxicity*; D016019:Survival Analysis; D016896:Treatment Outcome; D010738:Type C Phospholipases / Q000633:toxicity*
D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens; D000077553:Edaravone; D000983:Antipyrine