title: Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin.
abstract: Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses human cells exclusively, owing to its receptor specificity for human CD59. We generated two transgenic mouse strains that express human CD59 either on erythrocytes (strain ThCD59(RBC)) or on endothelia (strain ThCD59(END)). Intravenous injection of ILY in ThCD59(RBC) mice induced acute intravascular hemolysis, leading to reduced nitric oxide bioavailability, increased platelet activation and rapid death. In ThCD59(END) mice, ILY induced rapid endothelial damage, leading to acute death and disseminated intravascular coagulation. Additionally, we show that human serum contains ILY-specific neutralizing antibodies not found in any other animal species. Together, these results suggest that this new rapid conditional targeted ILY-mediated cell ablation technique can be used in combination with any available transgenic expression system to study the physiologic role of specific cell populations.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Hu
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ferris
authors.forename: Rodney K
authors.initials: RK
authors.lastname: Tweten
authors.forename: Gongxiong
authors.initials: G
authors.lastname: Wu
authors.forename: Svetlana
authors.initials: S
authors.lastname: Radaeva
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qin
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism* / Q000494:pharmacology; D001430:Bacteriocins / Q000378:metabolism* / Q000494:pharmacology; D018957:CD59 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D004727:Endothelium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013045:Species Specificity; D034367:Streptococcus intermedius / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001430:Bacteriocins; D018957:CD59 Antigens; D007074:Immunoglobulin G; D011994:Recombinant Proteins; C403910:intermedilysin protein, Streptococcus intermedius; D014841:von Willebrand Factor; D009569:Nitric Oxide