title: Lethal toxin of Bacillus anthracis causes apoptosis of macrophages.
abstract: Lethal toxin is a major anthrax virulence factor, causing the rapid death of experimental animals. Lethal toxin can enter most cell types, but only certain macrophages and cell lines are susceptible to toxin-mediated cytolysis. We have shown that in murine RAW 264.7 cells, sublytic amounts of lethal toxin trigger intracellular signaling events typical for apoptosis, including changes in membrane permeability, loss of mitochondrial membrane potential, and DNA fragmentation. The cells were protected from the toxin by specific inhibitors of caspase-1, -2, -3, -4, -6, and -8. Phagocytic activity of macrophages was inhibited by sublytic concentrations of lethal toxin. Infection of cells with anthrax (Sterne) spores impaired their bactericidal capacity, which could be reversed by a lethal toxin inhibitor, bestatin. We suggest that apoptosis rather than direct lysis is biologically relevant to lethal toxin intracellular activity.
authors.affiliation: Hadron Advanced Biosystems, Inc., 10900 University Boulevard, MSN 1A8, Manassas, VA 20110, USA. serguei.popov@hadron.com
authors.forename: Serguei G
authors.initials: SG
authors.lastname: Popov
authors.forename: Rafael
authors.initials: R
authors.lastname: Villasmil
authors.forename: Jessica
authors.initials: J
authors.lastname: Bernardi
authors.forename: Edith
authors.initials: E
authors.lastname: Grene
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cardwell
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wu
authors.forename: Darya
authors.initials: D
authors.lastname: Alibek
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.forename: Ken
authors.initials: K
authors.lastname: Alibek
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D017209:Apoptosis / Q000187:drug effects*; D001408:Bacillus anthracis; D001427:Bacterial Toxins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C030325:anthrax toxin; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9