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CA-074Me protection against anthrax lethal toxin

Zachary L Newman1, Stephen H Leppla, Mahtab Moayeri

  • 1Bacterial Toxins and Therapeutics Section, Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Infection and Immunity
|July 29, 2009
PubMed

Insights

Anthrax lethal toxin (LT) triggers the NLRP1b inflammasome via lysosomal membrane permeabilization and cathepsin B activity. This process is crucial for macrophage cell death and caspase-1 activation.

Area of Science:

  • Immunology
  • Cell Biology
  • Toxicology

Background:

  • Anthrax lethal toxin (LT) activates the NLRP1b inflammasome and caspase-1 in macrophages, but the precise mechanism remains unclear.
  • Lysosomal membrane permeabilization (LMP) and cathepsin B activity are implicated in inflammasome activation by other stimuli.

Purpose of the Study:

  • To elucidate the role of lysosomal membrane permeabilization and cathepsin B in LT-induced NLRP1b inflammasome activation.
  • To investigate the mechanism by which LT activates the NLRP1b inflammasome in macrophages.

Main Methods:

  • Utilized CA-074Me, a cathepsin B inhibitor, and RNA interference for cathepsin B knockdown.
  • Assessed LT translocation, potassium efflux, proteasome activity, and caspase-1 activation.
  • Monitored lysosomal membrane permeabilization and cathepsin B cytoplasmic activity.

Main Results:

  • LT-induced NLRP1b inflammasome activation involves lysosomal membrane permeabilization and subsequent cathepsin B activity.
  • CA-074Me protected macrophages from LT-induced cell death and inhibited caspase-1 activation.
  • Cathepsin B knockdown did not prevent cell death, suggesting CA-074Me acts on other proteases.
  • CA-074Me acted downstream of LT translocation, K(+) efflux, and proteasome activity.

Conclusions:

  • Lysosomal membrane permeabilization and cathepsin B activity are key events in LT-mediated NLRP1b inflammasome activation.
  • CA-074Me's protective effect suggests a broader role in inhibiting proteases released during LMP.
  • LMP is likely involved in the initial activation of the NLRP1b inflammasome by anthrax lethal toxin.

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