title: Shiga toxin 2-induced intestinal pathology in infant rabbits is A-subunit dependent and responsive to the tyrosine kinase and potential ZAK inhibitor imatinib.
abstract: Shiga toxin producing Escherichia coli (STEC) are a major cause of food-borne illness worldwide. However, a consensus regarding the role Shiga toxins play in the onset of diarrhea and hemorrhagic colitis (HC) is lacking. One of the obstacles to understanding the role of Shiga toxins to STEC-mediated intestinal pathology is a deficit in small animal models that perfectly mimic human disease. Infant rabbits have been previously used to study STEC and/or Shiga toxin-mediated intestinal inflammation and diarrhea. We demonstrate using infant rabbits that Shiga toxin-mediated intestinal damage requires A-subunit activity, and like the human colon, that of the infant rabbit expresses the Shiga toxin receptor Gb(3). We also demonstrate that Shiga toxin treatment of the infant rabbit results in apoptosis and activation of p38 within colonic tissues. Finally we demonstrate that the infant rabbit model may be used to test candidate therapeutics against Shiga toxin-mediated intestinal damage. While the p38 inhibitor SB203580 and the ZAK inhibitor DHP-2 were ineffective at preventing Shiga toxin-mediated damage to the colon, pretreatment of infant rabbits with the drug imatinib resulted in a decrease of Shiga toxin-mediated heterophil infiltration of the colon. Therefore, we propose that this model may be useful in elucidating mechanisms by which Shiga toxins could contribute to intestinal damage in the human.
authors.affiliation: Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, and Tufts University School of Medicine Boston, MA, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Stone
authors.forename: Cheleste M
authors.initials: CM
authors.lastname: Thorpe
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Fumiko
authors.initials: F
authors.lastname: Obata
authors.forename: Aimee
authors.initials: A
authors.lastname: Vozenilek
authors.forename: Glynis L
authors.initials: GL
authors.lastname: Kolling
authors.forename: Anne V
authors.initials: AV
authors.lastname: Kane
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Magun
authors.forename: Dakshina M
authors.initials: DM
authors.lastname: Jandhyala
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001549:Benzamides / Q000378:metabolism*; D000068877:Imatinib Mesylate; D007422:Intestines / Q000187:drug effects* / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases; D010879:Piperazines / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011494:Protein Kinases / Q000008:administration & dosage*; D021122:Protein Subunits / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000378:metabolism*; D011817:Rabbits; D022641:Shiga Toxin 2 / Q000633:toxicity*; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D011743:Pyrimidines; D022641:Shiga Toxin 2; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human