Abstract
Clostridium septicum is the causative agent of atraumatic gas gangrene, with α-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host’s innate immune response is poorly defined, although α-toxin-intoxicated muscle cells undergo cellular oncosis, characterised by mitochondrial dysfunction and release of reactive oxygen species. Nonetheless, the signalling events that occur prior to the initiation of oncosis are poorly characterised. Our aims were to characterise the ability of α-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified α-toxin activated the extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 arms of the MAPK pathway and stimulated the release of TNF-α in a dose-dependent manner. Studies using inhibitors of all three MAPK components suggested that activation of ERK occurred in a Ras-c-Raf dependent manner, whereas activation of JNK and p38 occurred by a Ras-independent mechanism. Toxin-mediated activation was dependent on efficient receptor binding and pore formation and on an influx of extracellular calcium ions. In the mouse myonecrosis model we showed that the MAPK pathway was activated in tissues of infected mice, implying that it has an important role in the disease process.
Highlights
Clostridium septicum is a Gram-positive, spore-forming anaerobic rod that is present in the environment and in the gastrointestinal tract of humans and animals [1,2]
The mechanism by which C. septicum interacts with and modulates the host’s innate immune response is not well understood; it is different to the process observed in C. perfringens infections, even though both of these necrotic diseases are characterised by a paucity of polymorphonuclear leukocytes (PMNs) at the site of infection [7,32,33]
In this report we have shown that C. septicum α-toxin is capable of activating the mitogen activated protein kinase (MAPK) pathway by the Ras-c-Raf route, providing a mechanism by which this toxin may modulate and regulate cellular fate
Summary
Clostridium septicum is a Gram-positive, spore-forming anaerobic rod that is present in the environment and in the gastrointestinal tract of humans and animals [1,2]. C. septicum is the causative agent of both traumatic and atraumatic gas gangrene and disease is usually initiated when wounds become contaminated with either vegetative cells or spores. The major virulence factor produced by C. septicum is α-toxin, a β-barrel pore-forming cytolysin [5,6]. Mutagenesis studies have shown that α-toxin is the primary virulence factor in C. septicum-mediated disease since deletion of the α-toxin structural gene (csa) renders the resultant strain avirulent in a mouse myonecrosis model [7]. Infection with C. septicum mimics some of the features seen in Clostridium perfringens-mediated gas gangrene, in particular, the absence of polymorphonuclear leukocytes (PMNs) within the site of infection [7], the mechanism by which this process occurs in
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