title: Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice.
abstract: Bacillus anthracis edema toxin (ET), an adenylyl cyclase, is an important virulence factor that contributes to anthrax disease. The role of ET in anthrax pathogenesis is, however, poorly understood. Previous studies using crude toxin preparations associated ET with subcutaneous edema, and ET-deficient strains of B. anthracis showed a reduction in virulence. We report the first comprehensive study of ET-induced pathology in an animal model. Highly purified ET caused death in BALB/cJ mice at lower doses and more rapidly than previously seen with the other major B. anthracis virulence factor, lethal toxin. Observations of gross pathology showed intestinal intralumenal fluid accumulation followed by focal hemorrhaging of the ileum and adrenal glands. Histopathological analyses of timed tissue harvests revealed lesions in several tissues including adrenal glands, lymphoid organs, bone, bone marrow, gastrointestinal mucosa, heart, and kidneys. Concomitant blood chemistry analyses supported the induction of tissue damage. Several cytokines increased after ET administration, including granulocyte colony-stimulating factor, eotaxin, keratinocyte-derived cytokine, MCP-1/JE, interleukin-6, interleukin-10, and interleukin-1beta. Physiological measurements also revealed a concurrent hypotension and bradycardia. These studies detail the extensive pathological lesions caused by ET and suggest that it causes death due to multiorgan failure.
authors.affiliation: National Institute of Allergy and Infectious Diseases, Office of Research Services, National Institutes of Health, 30 Convent Dr., Building 30, Room 303, Bethesda, MD 20892-4349, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Firoved
authors.forename: Georgina F
authors.initials: GF
authors.lastname: Miller
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Rahul
authors.initials: R
authors.lastname: Kakkar
authors.forename: Yuequan
authors.initials: Y
authors.lastname: Shen
authors.forename: Jason F
authors.initials: JF
authors.lastname: Wiggins
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
mesh_terms: D000262:Adenylyl Cyclases / Q000633:toxicity; D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D001853:Bone Marrow / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000473:pathology; D006470:Hemorrhage; D007082:Ileum / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009102:Multiple Organ Failure; D009206:Myocardium / Q000473:pathology; D037521:Virulence Factors / Q000633:toxicity
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D037521:Virulence Factors; C030325:anthrax toxin; D000262:Adenylyl Cyclases