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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.<\/jats:p>","DOI":"10.1128\/iai.00051-06","type":"journal-article","created":{"date-parts":[[2006,6,21]],"date-time":"2006-06-21T23:10:29Z","timestamp":1150931429000},"page":"3707-3714","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Oxidized ATP Protection against Anthrax Lethal Toxin"],"prefix":"10.1128","volume":"74","author":[{"given":"Mahtab","family":"Moayeri","sequence":"first","affiliation":[{"name":"Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine E.","family":"Wickliffe","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason F.","family":"Wiggins","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen H.","family":"Leppla","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/424853"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026043387223"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.12.9645-9655.1998"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/116.3.377"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705470"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.21.7972"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(88)65014-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.0031"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.19.111301.140655"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.6.C1793"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00593.2003"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062160399"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(84)80297-5"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705469"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400341"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.3.587"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00066a008"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117770"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.4049\/jimmunol.159.3.1451","volume":"159","year":"1997","unstructured":"Ferrari, D., P. 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