title: Fabry disease in mice protects against lethal disease caused by Shiga toxin-expressing enterohemorrhagic Escherichia coli.
abstract: Fabry disease is an X-linked recessive disorder in which affected persons lack alpha-galactosidase A (alpha -GalA), which leads to excess glycosphingolipids in tissues, mainly globotriaosylceramide (Gb3). Gb3 is the cellular receptor for Shiga toxin (Stx), the primary virulence factor of enterohemorrhagic Escherichia coli. alpha-GalA-knockout mice were significantly protected against lethal intraperitoneal doses of Stx2 or oral doses of Stx2-expressing bacteria, compared with wild-type (wt) control mice. Kidneys of moribund wt mice revealed tubular necrosis, but no histopathologic changes were observed in Gb3-overexpressing mice. Reducing Gb3 levels in alpha-GalA-knockout mice by the intravenous injection of recombinant human alpha-GalA restored the susceptibility of knockout mice to lethal doses of Stx2. These results suggest that excess amounts of Gb3 in alpha-GalA-deficient mice may impair toxin delivery to susceptible tissues.
authors.affiliation: Infectious Disease Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Salvatore A
authors.initials: SA
authors.lastname: Cilmi
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Karalius
authors.forename: Wendy
authors.initials: W
authors.lastname: Choy
authors.forename: R Neal
authors.initials: RN
authors.lastname: Smith
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004927:Escherichia coli Infections / Q000473:pathology*; D019453:Escherichia coli O157 / Q000378:metabolism*; D000795:Fabry Disease; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022603:Shiga Toxins / Q000008:administration & dosage / Q000633:toxicity*; D014281:Trihexosylceramides / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D022603:Shiga Toxins; D014281:Trihexosylceramides; C018549:globotriaosylceramide