Investigation Of Anthrax-Lethal Toxin Induced Cell Death.

Overview

B. anthracis lethal toxin (LT) is one of numerous bacterial products that induce rapid cellular lysis of macrophages and dendritic cells. The host response is initiated by cytoplasmic recognition of a danger signal, such as microbial invasion or stress, by Nod-like receptors (NLRs). NLRs trigger caspase-1-dependent (pyroptosis) or -independent (pyronecrosis) cellular lysis depending on the NLR and stimulus. LT activity is recognized by a subset of alleles of the NLR protein Nlrp1b, resulting in caspase-1 ...
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Overview

B. anthracis lethal toxin (LT) is one of numerous bacterial products that induce rapid cellular lysis of macrophages and dendritic cells. The host response is initiated by cytoplasmic recognition of a danger signal, such as microbial invasion or stress, by Nod-like receptors (NLRs). NLRs trigger caspase-1-dependent (pyroptosis) or -independent (pyronecrosis) cellular lysis depending on the NLR and stimulus. LT activity is recognized by a subset of alleles of the NLR protein Nlrp1b, resulting in caspase-1 dependent pyroptosis. This dissertation describes an investigation into the signal that initiates Nlrp1b-inflammasome activation and events that occur following LT intoxication that mediates cell lysis. Directed approaches were used to test our hypotheses that lysosomal destabilization functions in toxicity and that toxin-induced pore formation may facilitate pyroptosis. In support of our hypothesis, LT induces lysosomal membrane permeabilization (LMP) and the lysosomal protease, cathepsin B, is released and active in the cytosol during pyroptosis. Cathepsin inhibitors block cell death, implicating a causal role for this family of proteases in pyroptosis. Bid, a modulator of LMP, is converted to its active form during LT-mediated pyroptosis. We discovered that anthrax toxin pore formation, with or without MAPK signaling disruption, was insufficient to induce pyroptosis, suggesting that additional signals are required. Unbiased approaches were employed including proteomic analysis of LT-treated cells, genetic screens to uncover genes that modulate LT toxicity, and Bacillus anthracis versus human whole genome yeast-two hybrid analysis. A novel interaction between B. anthracis lethal factor and APLP2 is described. Additionally, we discovered a cDNA that, when expressed in murine macrophages, protects from LT, likely though a mitochodrially-derived peptide. Our data suggest that lysosomal and mitochondrial membrane instability are key events in LT-induced pyroptosis. We also demonstrate that cathepsins are shared mediators of pyroptosis and pyronecrosis and divulge a new role for LMP in the cellular response to bacterial pathogens and stress.
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Product Details

  • ISBN-13: 9781243673602
  • Publisher: BiblioLabsII
  • Publication date: 9/7/2011
  • Pages: 214
  • Product dimensions: 7.44 (w) x 9.69 (h) x 0.45 (d)

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