PMID- 25675415
OWN - NLM
STAT- MEDLINE
DCOM- 20151020
LR  - 20191210
IS  - 2072-6651 (Electronic)
IS  - 2072-6651 (Linking)
VI  - 7
IP  - 2
DP  - 2015 Feb 10
TI  - The pore-forming alpha-toxin from clostridium septicum activates the MAPK pathway in 
      a Ras-c-Raf-dependent and independent manner.
PG  - 516-34
LID - 10.3390/toxins7020516 [doi]
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.
FAU - Chakravorty, Anjana
AU  - Chakravorty A
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      achak27@gmail.com.
FAU - Awad, Milena M
AU  - Awad MM
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      milena.awad@monash.edu.
FAU - Cheung, Jackie K
AU  - Cheung JK
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      jackie.k.cheung@monash.edu.
FAU - Hiscox, Thomas J
AU  - Hiscox TJ
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      thomas.hiscox@monash.edu.
FAU - Lyras, Dena
AU  - Lyras D
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      dena.lyras@monash.edu.
FAU - Rood, Julian I
AU  - Rood JI
AD  - Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. 
      julian.rood@monash.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150210
PL  - Switzerland
TA  - Toxins (Basel)
JT  - Toxins
JID - 101530765
RN  - 0 (Bacterial Toxins)
RN  - 0 (Pore Forming Cytotoxic Proteins)
RN  - 0 (hemolytic toxin, Clostridium septicum)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (Ras-dependent mitogen-activated protein kinase kinase kinase)
SB  - IM
MH  - Animals
MH  - Bacterial Toxins/genetics/*toxicity
MH  - Cell Survival/drug effects
MH  - Chlorocebus aethiops
MH  - Clostridium septicum/*chemistry
MH  - Dose-Response Relationship, Drug
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mice
MH  - Muscle, Skeletal/enzymology
MH  - Pore Forming Cytotoxic Proteins/genetics/*toxicity
MH  - Proto-Oncogene Proteins c-raf/*metabolism
MH  - Sepsis/enzymology/microbiology
MH  - Spleen/enzymology
MH  - Vero Cells
PMC - PMC4344638
EDAT- 2015/02/13 06:00
MHDA- 2015/10/21 06:00
PMCR- 2015/02/01
CRDT- 2015/02/13 06:00
PHST- 2014/11/24 00:00 [received]
PHST- 2015/02/02 00:00 [accepted]
PHST- 2015/02/13 06:00 [entrez]
PHST- 2015/02/13 06:00 [pubmed]
PHST- 2015/10/21 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - toxins7020516 [pii]
AID - toxins-07-00516 [pii]
AID - 10.3390/toxins7020516 [doi]
PST - epublish
SO  - Toxins (Basel). 2015 Feb 10;7(2):516-34. doi: 10.3390/toxins7020516.