title: Shiga Toxin (Stx) Type 1a Reduces the Oral Toxicity of Stx Type 2a.
abstract: BACKGROUND
  Shiga toxin (Stx) is the primary virulence factor of Stx-producing Escherichia coli (STEC). STEC can produce Stx1a and/or Stx2a, which are antigenically distinct. However, Stx2a-producing STEC are associated with more severe disease than strains producing both Stx1a and Stx2a.
  
  
  RESULTS
  To address the hypothesis that the reason for the association of Stx2a with more severe disease is because Stx2a crosses the intestinal barrier with greater efficiency that Stx1a, we covalently labeled Stx1a and Stx2a with Alexa Fluor 750 and determined the ex vivo fluorescent intensity of murine systemic organs after oral intoxication. Surprisingly, both Stxs exhibited similar dissemination patterns and accumulated in the kidneys. We next cointoxicated mice to determine whether Stx1a could impede Stx2a. Cointoxication resulted in increased survival and an extended mean time to death, compared with intoxication with Stx2a only. The survival benefit was dose dependent, with the greatest effect observed when 5 times more Stx1a than Stx2a was delivered, and was amplified when Stx1a was delivered 3 hours prior to Stx2a. Cointoxication with an Stx1a active site toxoid also reduced Stx2a toxicity.
  
  
  CONCLUSIONS
  These studies suggest that Stx1a reduces Stx2a-mediated toxicity, a finding that may explain why STEC that produce only Stx2a are associated with more severe disease than strains producing Stx1a and Stx2a.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Russo
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Melton-Celsa
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Alison D
authors.initials: AD
authors.lastname: O'Brien
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D022622:Shiga Toxin 1 / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D022641:Shiga Toxin 2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D054323:Shiga-Toxigenic Escherichia coli; D016019:Survival Analysis
chemical_list: D022622:Shiga Toxin 1; D022641:Shiga Toxin 2
keywords: Escherichia coli; STEC; Shiga toxin; Stx1a; Stx2a; oral intoxication