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Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum
Catherine L Kennedy1, Danielle J Smith, Dena Lyras
1Australian Bacterial Pathogenesis Research Program, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Plos Pathogens
|July 18, 2009
Summary
Clostridium septicum alpha-toxin induces programmed necrosis by forming calcium-permeable pores in cells. This pore formation triggers a cascade of events leading to cell death, distinct from apoptosis.
Area of Science:
- Cell Biology
- Microbiology
- Toxicology
Background:
- Programmed necrosis is a cell death pathway implicated in various injuries, but its role in bacterial exotoxin exposure is understudied.
- Clostridium septicum alpha-toxin is a known cytotoxin, yet its precise mechanism of cell death induction remains unclear.
Purpose of the Study:
- To elucidate the cell death mechanism induced by Clostridium septicum alpha-toxin.
- To investigate the role of calcium influx and downstream events in alpha-toxin-mediated cell death.
Main Methods:
- Exposure of murine myoblast cells to Clostridium septicum alpha-toxin.
- Measurement of intracellular calcium levels.
- Assessment of apoptosis markers, lysosomal integrity, mitochondrial function, and ATP levels.
- Analysis of High Mobility Group Box 1 (HMGB1) release.
Main Results:
- Alpha-toxin formed calcium-permeable pores, increasing intracellular calcium.
- Calcium influx triggered calpain activation and cathepsin release, consistent with programmed necrosis, not apoptosis.
- Mitochondrial dysfunction, increased reactive oxygen species (ROS), and reduced ATP levels were observed.
- Nuclear release of the immunostimulatory protein HMGB1 occurred.
Conclusions:
- Clostridium septicum alpha-toxin induces programmed necrosis through calcium-permeable pore formation.
- This multifaceted necrotic response is crucial for C. septicum-mediated myonecrosis and sepsis.
- Pore-forming toxins may represent a significant mechanism for inducing programmed necrosis.
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