{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T03:08:59Z","timestamp":1776481739207,"version":"3.51.2"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013017","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Aging Institute of University of Pittsburgh School of Medicine"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI170574"],"award-info":[{"award-number":["R01AI170574"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Anthrax lethal toxin (LT) and edema toxin (ET) are two of the major virulence factors of <jats:italic>Bacillus anthracis<\/jats:italic>, the causative pathogen of anthrax disease. While the roles of LT in anthrax pathogenesis have been extensively studied, the pathogenic mechanism of ET remains poorly understood. ET is a calmodulin-dependent adenylate cyclase that elevates intracellular cAMP by converting ATP to cAMP. Thus, it was postulated that the ET-induced <jats:italic>in vivo<\/jats:italic> toxicity is mediated by certain cAMP-dependent events. However, mechanisms linking cAMP elevation and ET-induced damage have not been established. Cholera toxin is another bacterial toxin that increases cAMP. This toxin is known to cause severe intestinal fluid secretion and dehydration by cAMP-mediated activation of protein kinase A (PKA), which in turn activates cystic fibrosis transmembrane conductance regulator (CFTR). The cAMP-activated PKA phosphorylation of CFTR on the surface of intestinal epithelial cells leads to an efflux of chloride ions accompanied by secretion of H<jats:sub>2<\/jats:sub>O into the intestinal lumen, causing rapid fluid loss, severe diarrhea and dehydration. Due to similar <jats:italic>in vivo<\/jats:italic> effects, it was generally believed that ET and cholera toxin would exhibit a similar pathogenic mechanism. Surprisingly, in this work, we found that cAMP-mediated PKA\/CFTR activation is not essential for ET to exert its <jats:italic>in vivo<\/jats:italic> toxicity. Instead, our data suggest that ET-induced ATP depletion may play an important role in the toxin\u2019s pathogenesis.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013017","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T21:56:11Z","timestamp":1743544571000},"page":"e1013017","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["ATP depletion in anthrax edema toxin pathogenesis"],"prefix":"10.1371","volume":"21","author":[{"given":"Jie","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Ewing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zehua","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason R.","family":"Kennerdell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toren","family":"Finkel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen H.","family":"Leppla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-1069","authenticated-orcid":true,"given":"Shihui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"ppat.1013017.ref001","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ijmm.2007.09.007","article-title":"Bacillus anthracis: balancing innocent research with dual-use potential","volume":"298","author":"MJ Hudson","year":"2008","journal-title":"Int J Med Microbiol"},{"key":"ppat.1013017.ref002","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/B978-0-12-382219-2.00282-9","article-title":"Chapter 281 - anthrax lethal factor.","volume-title":"Handbook of proteolytic enzymes","author":"SH. 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