The pore-forming alpha-toxin from clostridium septicum activates the MAPK pathway in a Ras-c-Raf-dependent and independent manner

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Abstract

Clostridium septicum is the causative agent of atraumatic gas gangrene, with alpha-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host s innate immune response is poorly defined, although alpha-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 alpha-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified alpha-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-alpha 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.
Original languageEnglish
Pages (from-to)516 - 534
Number of pages19
JournalToxins
Volume7
Issue number2
DOIs
Publication statusPublished - 2015

Cite this

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title = "The pore-forming alpha-toxin from clostridium septicum activates the MAPK pathway in a Ras-c-Raf-dependent and independent manner",
abstract = "Clostridium septicum is the causative agent of atraumatic gas gangrene, with alpha-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host s innate immune response is poorly defined, although alpha-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 alpha-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified alpha-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-alpha 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.",
author = "Anjana Chakravorty and Awad, {Milena M} and Cheung, {Jackie K T} and Hiscox, {Thomas J} and Dena Lyras and Rood, {Julian I}",
year = "2015",
doi = "10.3390/toxins7020516",
language = "English",
volume = "7",
pages = "516 -- 534",
journal = "Toxins",
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publisher = "MDPI",
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TY - JOUR

T1 - The pore-forming alpha-toxin from clostridium septicum activates the MAPK pathway in a Ras-c-Raf-dependent and independent manner

AU - Chakravorty, Anjana

AU - Awad, Milena M

AU - Cheung, Jackie K T

AU - Hiscox, Thomas J

AU - Lyras, Dena

AU - Rood, Julian I

PY - 2015

Y1 - 2015

N2 - Clostridium septicum is the causative agent of atraumatic gas gangrene, with alpha-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host s innate immune response is poorly defined, although alpha-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 alpha-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified alpha-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-alpha 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.

AB - Clostridium septicum is the causative agent of atraumatic gas gangrene, with alpha-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host s innate immune response is poorly defined, although alpha-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 alpha-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified alpha-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-alpha 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.

UR - http://www.mdpi.com/2072-6651/7/2/516/htm

U2 - 10.3390/toxins7020516

DO - 10.3390/toxins7020516

M3 - Article

VL - 7

SP - 516

EP - 534

JO - Toxins

JF - Toxins

SN - 2072-6651

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ER -