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Oxidized ATP protection against anthrax lethal toxin.

Abstract
Bacillus anthracis lethal toxin (LT) induces rapid lysis (<90 min) of murine macrophages from certain inbred strains. The mechanism for LT-induced cytolysis is currently unknown. We hypothesized that the ATP-activated macrophage P2X7 receptors implicated in nucleotide-mediated macrophage lysis could play a role in LT-mediated cytolysis and discovered that a potent P2X7 antagonist, oxidized ATP (o-ATP), protects macrophages against LT. Other P2X7 receptor antagonists, however, had no effect on LT function, while oxidized nucleotides, o-ADP, o-GTP, and o-ITP, which did not act as receptor ligands, provided protection. Cleavage of the LT substrates, the mitogen-activated protein kinases, was inhibited by o-ATP in RAW274.6 macrophages and CHO cells. We investigated the various steps in the intoxication pathway and found that binding of the protective-antigen (PA) component of LT to cells and the enzymatic proteolytic ability of the lethal factor (LF) component of LT were unaffected by o-ATP. Instead, the drug inhibited formation of the sodium dodecyl sulfate-resistant PA oligomer, which occurs in acidified endosomes, but did not prevent cell surface PA oligomerization, as evidenced by binding and translocation of LF to a protease-resistant intracellular location. We found that o-ATP also protected cells from anthrax edema toxin and diphtheria toxin, which also require an acidic environment for escape from endosomes. Confocal microscopy using pH-sensitive fluorescent dyes showed that o-ATP increased endosomal pH. Finally, BALB/cJ mice injected with o-ATP and LT were completely protected against lethality.
AuthorsMahtab Moayeri, Katherine E Wickliffe, Jason F Wiggins, Stephen H Leppla
JournalInfection and immunity (Infect Immun) Vol. 74 Issue 7 Pg. 3707-14 (Jul 2006) ISSN: 0019-9567 [Print] United States
PMID16790743 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Antigens, Bacterial
  • Bacterial Toxins
  • anthrax toxin
  • 2',3'-dialdehyde ATP
  • Adenosine Triphosphate
Topics
  • Adenosine Triphosphate (analogs & derivatives, metabolism, physiology)
  • Animals
  • Antigens, Bacterial (toxicity)
  • Bacterial Toxins (antagonists & inhibitors, toxicity)
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Macrophages (drug effects, metabolism, physiology)
  • Mice
  • Mice, Inbred BALB C
  • Oxidation-Reduction

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