Oxidized Atp Protection Against Anthrax Lethal Toxin.
From: Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Infection and immunity
- Publish Date: Jul 2006
- ISSN: 0019-9567
- Volume: 74
- Issue: 7
- Pages: 3707-14
- Medium: Print
- Language: English
- Citation (JAMA): Moayeri Mahtab, Wickliffe Katherine E, Wiggins Jason F, et al. Oxidized Atp Protection Against Anthrax Lethal Toxin.. Infect. Immun. Jul 2006;74:3707-14
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.
Mesh Headings (Keywords): Adenosine Triphosphate, Animals, Antigens, Bacterial, Bacterial Toxins, CHO Cells, Cell Line, Cricetinae, Cricetulus, Macrophages, Mice, Mice, Inbred BALB C, Oxidation-Reduction
Check for Full Text / PubMed Unique Identifier (PMID): 16790743
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