title: Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature.
abstract: Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.
authors.affiliation: Vascular Biology Program, Children's Hospital Boston and Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Bolcome
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Sullivan
authors.forename: René
authors.initials: R
authors.lastname: Zeller
authors.forename: Adam P
authors.initials: AP
authors.lastname: Barker
authors.forename: R John
authors.initials: RJ
authors.lastname: Collier
authors.forename: Joanne
authors.initials: J
authors.lastname: Chan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D040262:Receptors, Vascular Endothelial Growth Factor