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Infection and Immunity, October 2009, p. 4327-4336, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00730-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CA-074Me Protection against Anthrax Lethal Toxin{triangledown}

Zachary L. Newman, Stephen H. Leppla, and Mahtab Moayeri*

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

Received 26 June 2009/ Returned for modification 11 July 2009/ Accepted 17 July 2009

Anthrax lethal toxin (LT) activates the NLRP1b (NALP1b) inflammasome and caspase-1 in macrophages from certain inbred mouse strains, but the mechanism by which this occurs is poorly understood. We report here that similar to several NLRP3 (NALP3, cryopyrin)-activating stimuli, LT activation of the NLRP1b inflammasome involves lysosomal membrane permeabilization (LMP) and subsequent cytoplasmic cathepsin B activity. CA-074Me, a potent cathepsin B inhibitor, protects LT-sensitive macrophages from cell death and prevents the activation of caspase-1. RNA interference knockdown of cathepsin B expression, however, cannot prevent LT-mediated cell death, suggesting that CA-074Me may also act on other cellular proteases released during LMP. CA-074Me appears to function downstream of LT translocation to the cytosol (as assessed by mitogen-activated protein kinase kinase cleavage), K+ effluxes, and proteasome activity. The initial increase in cytoplasmic activity of cathepsin B occurs at the same time or shortly before caspase-1 activation but precedes a larger-scale lysosomal destabilization correlated closely with cytolysis. We present results suggesting that LMP may be involved in the activation of the NLRP1b inflammasome.

* Corresponding author. Mailing address: Building 33, Room 1W20B, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-1821. Fax: (301) 480-0326. E-mail: mmoayeri{at}niaid.nih.gov

{triangledown} Published ahead of print on 27 July 2009.

Editor: S. R. Blanke

Infection and Immunity, October 2009, p. 4327-4336, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00730-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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