title: Lipopolysaccharide renders transgenic mice expressing human serum amyloid P component sensitive to Shiga toxin 2.
abstract: Transgenic C57BL/6 mice expressing human serum amyloid P component (HuSAP) are resistant to Shiga toxin 2 (Stx2) at dosages that are lethal in HuSAP-negative wild-type mice. However, it is well established that Stx2 initiates extra-intestinal complications such as the haemolytic-uremic syndrome despite the presence of HuSAP in human sera. We now demonstrate that co-administering purified Escherichia coli O55 lipopolysaccharide (LPS), at a dosage of 300 ng/g body weight, to HuSAP-transgenic mice increases their susceptibility to the lethal effects of Stx2. The enhanced susceptibility to Stx2 correlated with an increased expression of genes encoding the pro-inflammatory cytokine TNFα and chemokines of the CXC and CC families in the kidneys of LPS-treated mice, 48 hours after the Stx2/LPS challenge. Co-administering the glucocorticoid dexamethasone, but not the LPS neutralizing cationic peptide LL-37, protected LPS-sensitized HuSAP-transgenic mice from lethal doses of Stx2. Dexamethasone protection was specifically associated with decreased expression of the same inflammatory mediators (CXC and CC-type chemokines and TNFα) linked to enhanced susceptibility caused by LPS. The studies reveal further details about the complex cascade of host-related events that are initiated by Stx2 as well as establish a new animal model system in which to investigate strategies for diminishing serious Stx2-mediated complications in humans infected with enterohemorrhagic E. coli strains.
authors: Department of Microbiology, Immunology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Thomas P
authors: TP
authors: Griener
authors: Jonathan G
authors: JG
authors: Strecker
authors: Romney M
authors: RM
authors: Humphries
authors: George L
authors: GL
authors: Mulvey
authors: Carmen
authors: C
authors: Fuentealba
authors: Robert E W
authors: RE
authors: Hancock
authors: Glen D
authors: GD
authors: Armstrong
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding / Q000187:drug effects; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D022641:Shiga Toxin 2 / Q000276:immunology*; D016019:Survival Analysis; D015431:Weight Loss / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D000683:Serum Amyloid P-Component; D022641:Shiga Toxin 2