title: Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.
abstract: The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.
authors.affiliation: Pulmonary and Critical Care Division of the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Langer
authors.forename: Elizabeth Stewart
authors.initials: ES
authors.lastname: Duggan
authors.forename: John Leland
authors.initials: JL
authors.lastname: Booth
authors.forename: Vineet Indrajit
authors.initials: VI
authors.lastname: Patel
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Zander
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramani
authors.forename: Tibor Zoltan
authors.initials: TZ
authors.lastname: Veres
authors.forename: Frauke
authors.initials: F
authors.lastname: Prenzler
authors.forename: Katherina
authors.initials: K
authors.lastname: Sewald
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Williams
authors.forename: Kenneth Mark
authors.initials: KM
authors.lastname: Coggeshall
authors.forename: Shanjana
authors.initials: S
authors.lastname: Awasthi
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Dennis
authors.initials: D
authors.lastname: Burian
authors.forename: Jimmy Dale
authors.initials: JD
authors.lastname: Ballard
authors.forename: Armin
authors.initials: A
authors.lastname: Braun
authors.forename: Jordan Patrick
authors.initials: JP
authors.lastname: Metcalf
mesh_terms: D000199:Actins / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D000881:Anthrax / Q000382:microbiology / Q000473:pathology*; D000942:Antigens, Bacterial / Q000235:genetics / Q000633:toxicity*; D001408:Bacillus anthracis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000235:genetics / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000382:microbiology / Q000473:pathology*; D014774:Virulence
chemical_list: D000199:Actins; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors; D006899:Mixed Function Oxygenases; C419389:ASPH protein, human