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Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages
Zachary L Newman1, Devorah Crown, Stephen H Leppla
1Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Building 33, Room 1W20B, Bethesda, MD 20892, USA. newmanz@niaid.nih.gov
Biochemical and Biophysical Research Communications
|July 20, 2010
Summary
Anthrax lethal toxin (LT) activates caspase-1 in rat macrophages, similar to mice. Inhibiting proteasomes or caspase-1 protects rats from LT toxicity, confirming the Nlrp1 inflammasome
Area of Science:
- Immunology
- Microbiology
- Toxicology
Background:
- Anthrax lethal toxin (LT) is a key virulence factor of Bacillus anthracis.
- LT causes macrophage lysis in susceptible mouse strains via Nlrp1b inflammasome and caspase-1 activation.
- Rat macrophages exhibit varying sensitivity to LT, necessitating investigation into underlying mechanisms.
Purpose of the Study:
- To investigate if a similar Nlrp1 inflammasome pathway mediates LT-induced death in rat macrophages.
- To analyze the role of caspase-1 activation and proteasome activity in rat macrophage response to LT.
- To evaluate potential protective agents against LT toxicity in rat macrophages.
Main Methods:
- LT exposure on toxin-sensitive and resistant rat macrophages.
- Assessment of caspase-1 activation and proteasome activity.
- Evaluation of protective effects of lactacystin, quinidine, caspase-1 inhibitors, cathepsin B inhibitor, and heat shock.
- Monitoring of rat survival following LT challenge with proteasome inhibition.
Main Results:
- LT activated caspase-1 in sensitive rat macrophages, mirroring findings in mice.
- Caspase-1 activation was proteasome-dependent, and lactacystin protected macrophages and delayed rat death.
- Quinidine, caspase-1 inhibitors, CA-074Me, and heat shock also conferred protection against LT toxicity.
Conclusions:
- Rat macrophages possess a functional LT-responsive Nlrp1 inflammasome.
- Nlrp1 inflammasome activation is essential for LT-mediated rat macrophage lysis.
- The Nlrp1 inflammasome pathway contributes significantly to LT-induced animal mortality.
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