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Toxins 2015, 7(2), 516-534; doi:10.3390/toxins7020516

The Pore-Forming α-Toxin from Clostridium septicum Activates the MAPK Pathway in a Ras-c-Raf-Dependent and Independent Manner

Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editor: Vernon L. Tesh
Received: 24 November 2014 / Accepted: 2 February 2015 / Published: 10 February 2015
(This article belongs to the Section Bacterial Toxins)
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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. View Full-Text
Keywords: Clostridium septicum; mitogen-activated protein kinases; α-toxin; pathogenesis; pore-forming toxins; gas gangrene Clostridium septicum; mitogen-activated protein kinases; α-toxin; pathogenesis; pore-forming toxins; gas gangrene
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chakravorty, A.; Awad, M.M.; Cheung, J.K.; Hiscox, T.J.; Lyras, D.; Rood, J.I. The Pore-Forming α-Toxin from Clostridium septicum Activates the MAPK Pathway in a Ras-c-Raf-Dependent and Independent Manner. Toxins 2015, 7, 516-534.

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