title: Key tissue targets responsible for anthrax-toxin-induced lethality.
abstract: Bacillus anthracis, the causative agent of anthrax disease, is lethal owing to the actions of two exotoxins: anthrax lethal toxin (LT) and oedema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type-specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type-specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occurs through damage to distinct cell types; whereas targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Notably, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not seem to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems.
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. shliu@niaid.nih.gov
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.forename: Rasem J
authors.initials: RJ
authors.lastname: Fattah
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Wein
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
mesh_terms: D000818:Animals; D000881:Anthrax / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D060467:Disease Resistance / Q000235:genetics; D004487:Edema / Q000139:chemically induced; D042783:Endothelial Cells / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D000942:Antigens, Bacterial; C523013:Antxr2 protein, mouse; D001427:Bacterial Toxins; D018000:Receptors, Peptide; C030325:anthrax toxin