{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:38:50Z","timestamp":1790519930478,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,1,26]],"date-time":"2017-01-26T00:00:00Z","timestamp":1485388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"USDA-NIFA","award":["2012-68003-3015"],"award-info":[{"award-number":["2012-68003-3015"]}]},{"name":"Teijin Pharma Limite","award":["None"],"award-info":[{"award-number":["None"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal antibody against Shiga toxin (Stx) 2 for the prevention of brain damage, dysfunction, and death in a piglet EHEC infection model. Forty-five neonatal gnotobiotic piglets were inoculated orally with 3 \u00d7 109 colony-forming units of EHEC O157:H7 strain EDL933 (Stx1+, Stx2+) when 22\u201324 h old. At 24 h post-inoculation, piglets were intraperitoneally administered placebo or TMA-15 (0.3, 1.0 or 3.0 mg\/kg body weight). Compared to placebo (n = 10), TMA-15 (n = 35) yielded a significantly greater probability of survival, length of survival, and weight gain (p &lt;0.05). The efficacy of TMA-15 against brain lesions and death was 62.9% (p = 0.0004) and 71.4% (p = 0.0004), respectively. These results suggest that TMA-15 may potentially prevent or reduce vascular necrosis and infarction of the brain attributable to Stx2 in human patients acutely infected with EHEC. However, we do not infer that TMA-15 treatment will completely protect human patients infected with EHEC O157:H7 strains that produce both Stx1 and Stx2.<\/jats:p>","DOI":"10.3390\/toxins9020049","type":"journal-article","created":{"date-parts":[[2017,1,26]],"date-time":"2017-01-26T09:55:23Z","timestamp":1485424523000},"page":"49","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model"],"prefix":"10.3390","volume":"9","author":[{"given":"Rodney","family":"Moxley","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuho","family":"Tamura","sequence":"additional","affiliation":[{"name":"Teijin Pharma Limited, Pharmacology Research Department, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Marx","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Santiago-Mateo","sequence":"additional","affiliation":[{"name":"Canadian Food Inspection Agency, Lethbridge Laboratory, Box 640 TWP Rd 9-1, Lethbridge, AB T1J 3Z4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Valley Pathologists, Inc., 1100 South Main Street, Suite 308, Dayton, OH 45409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kaper, J.B., and O\u2019Brien, A.D. (2014). Overview and historical perspectives. Microbiol. Spectrum, 2.","DOI":"10.1128\/microbiolspec.EHEC-0028-2014"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1128\/CMR.00022-13","article-title":"Recent advances in understanding enteric pathogenic Escherichia coli","volume":"26","author":"Croxen","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1089\/fpd.2013.1704","article-title":"Global incidence of human Shiga toxin-producing Escherichia coli infections and deaths: A systematic review and knowledge synthesis","volume":"11","author":"Majowicz","year":"2014","journal-title":"Foodborne Pathog. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3201\/eid1701.P11101","article-title":"Foodborne illness acquired in the United States\u2014Major pathogens","volume":"17","author":"Scallan","year":"2011","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1128\/AAC.00343-09","article-title":"Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli","volume":"54","author":"Contrini","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/nrneph.2012.196","article-title":"Renal and neurological involvement in typical Shiga toxin-associated HUS","volume":"8","author":"Trachtman","year":"2012","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Karpman, D., and St\u00e5hl, A.L. (2014). Enterohemorrhagic Escherichia coli pathogenesis and the host response. Microbiol. Spectrum, 2.","DOI":"10.1128\/microbiolspec.EHEC-0009-2013"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"McWilliams, B.D., and Torres, A.G. (2014). Enterohemorrhagic Escherichia coli adhesins. Microbiol. Spectr., 2.","DOI":"10.1128\/microbiolspec.EHEC-0003-2013"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Stevens, M.P., and Frankel, G.M. (2014). The locus of enterocyte effacement and associated virulence factors of enterohemorrhagic Escherichia coli. Microbiol. Spectr., 2.","DOI":"10.1128\/microbiolspec.EHEC-0007-2013"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1128\/iai.51.3.953-956.1986","article-title":"Infection of gnotobiotic pigs with an Escherichia coli O157:H7 strain associated with an outbreak of hemorrhagic colitis","volume":"51","author":"Francis","year":"1986","journal-title":"Infect. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1093\/infdis\/154.4.712","article-title":"The pathogenesis of hemorrhagic colitis caused by Escherichia coli O157:H7 in gnotobiotic piglets","volume":"154","author":"Tzipori","year":"1986","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1172\/JCI116718","article-title":"The role of the eae gene of enterohemorrhagic Escherichia coli in intimate attachment in vitro and in a porcine model","volume":"92","author":"Donnenberg","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1128\/iai.63.9.3739-3744.1995","article-title":"Enterohemorrhagic Escherichia coli O157:H7 requires intimin to colonize the gnotobiotic pig intestine and to adhere to HEp-2 cells","volume":"63","author":"McKee","year":"1995","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Melton-Celsa, A.R. (2014). Shiga toxin (Stx) classification, structure, and function. Microbiol. Spectr., 2.","DOI":"10.1128\/microbiolspec.EHEC-0024-2013"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1128\/JCM.00860-12","article-title":"Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature","volume":"50","author":"Scheutz","year":"2012","journal-title":"J. Clin. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Obata, F., and Obrig, T. (2014). Role of Shiga\/Vero toxins in pathogenesis. Microbiol. Spectrum, 2.","DOI":"10.1128\/microbiolspec.EHEC-0005-2013"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1097\/MNH.0b013e328354a62e","article-title":"Shiga toxin-associated hemolytic uremic syndrome: Advances in pathogenesis and therapeutics","volume":"21","author":"Marsden","year":"2012","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1136\/jcp.41.10.1099","article-title":"Cerebral infection with Escherichia coli O157:H7 in humans and gnotobiotic piglets","volume":"41","author":"Tzipori","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1128\/iai.57.4.1339-1342.1989","article-title":"Edema disease-like brain lesions in gnotobiotic piglets infected with Escherichia coli serotype O157:H7","volume":"57","author":"Francis","year":"1989","journal-title":"Infect. Immun."},{"key":"ref_20","unstructured":"Karmali, M.A., and Goglio, A.G. (1994). Recent Advances in Verocytotoxin Producing Escherichia coli Infections, Elsevier Science B.V."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1128\/IAI.67.7.3645-3648.1999","article-title":"Antibody-based protection of gnotobiotic piglets infected with Escherichia coli O157:H7 against systemic complications associated with Shiga toxin 2","volume":"67","author":"Kondova","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1086\/317930","article-title":"Intervention with Shiga toxin (Stx) antibody after infection by Stx-producing Escherichia coli","volume":"183","author":"Matise","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Melton-Celsa, A.R., and O\u2019Brien, A.D. (2014). New therapeutic developments against Shiga toxin-producing Escherichia coli. Microbiol. Spectrum, 2.","DOI":"10.1128\/microbiolspec.EHEC-0013-2013"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1128\/IAI.67.11.5717-5722.1999","article-title":"Monoclonal antibody to Shiga toxin 2 which blocks receptor binding and neutralizes cytotoxicity","volume":"67","author":"Nakao","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1089\/153685902760173872","article-title":"Development of humanized monoclonal antibody TMA-15 which neutralizes Shiga toxin 2","volume":"21","author":"Kimura","year":"2002","journal-title":"Hybrid. Hybrid."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1086\/323082","article-title":"Efficacy of post infection treatment with anti\u2013Shiga toxin (Stx) 2 humanized monoclonal antibody TMA-15 in mice lethally challenged with Stx-producing Escherichia coli","volume":"184","author":"Yamagami","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1128\/IAI.01743-07","article-title":"Comparison of the contributions of heat-labile enterotoxin and heat-stable enterotoxin b to the virulence of enterotoxigenic Escherichia coli in F4ac receptor-positive young pigs","volume":"76","author":"Erume","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7338","DOI":"10.1128\/AEM.00755-07","article-title":"Differences in virulence among Escherichia coli O157:H7 strains isolated from human disease outbreaks and healthy cattle","volume":"73","author":"Baker","year":"2007","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.brainres.2006.04.119","article-title":"Hypoxic\/Ischemic models in newborn piglet: comparison of constant FiO2 versus variable FiO2 delivery","volume":"1100","author":"Foster","year":"2006","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1309\/UMW9-D06Q-M94Q-JGH2","article-title":"Gnotobiotic piglets develop thrombotic microangiopathy after oral infection with enterohemorrhagic Escherichia coli","volume":"118","author":"Gunzer","year":"2002","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1128\/IAI.73.1.612-616.2005","article-title":"Shiga-toxigenic Escherichia coli-inoculated neonatal piglets develop kidney lesions that are comparable to those in humans with hemolytic-uremic syndrome","volume":"73","author":"Pohlenz","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1128\/IAI.70.2.612-619.2002","article-title":"Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection","volume":"70","author":"Mukherjee","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4607","DOI":"10.1128\/IAI.73.8.4607-4613.2005","article-title":"Human antibody against Shiga toxin 2 administered to piglets after the onset of diarrhea due to Escherichia coli O157:H7 prevents fatal systemic complications","volume":"73","author":"Sheoran","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_34","unstructured":"Chae, C. (1992). Shiga-Like Toxin-II-Producing Escherichia coli O157:H7 Infection in Gnotobiotic Pigs. [Ph.D. Thesis, University of Nebraska Medical Center]."},{"key":"ref_35","unstructured":"Schmidt, V. (2015). Comparative Anatomy of the Pig Brain\u2014An Integrative Magnetic Resonance Imaging (MRI) Study of the Porcine Brain with Special Emphasis on the External Morphology of the Cerebral Cortex. [Ph.D. Thesis, University of Giessen]."},{"key":"ref_36","unstructured":"Kaper, J.B., and O\u2019Brien, A.D. (1998). Escherichia coli O157:H7 and Other Shiga Toxin-Producing E. coli Strains, American Society for Microbiology Press."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1128\/CMR.17.4.926-941.2004","article-title":"Antibody therapy in the management of Shiga toxin-induced hemolytic uremic syndrome","volume":"17","author":"Tzipori","year":"2004","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ritchie, J.M. (2014). Animal models of enterohemorrhagic Escherichia coli infection. Microbiol. Spectr., 2.","DOI":"10.1128\/microbiolspec.EHEC-0022-2013"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1177\/088307388900400206","article-title":"Neurological complications of hemolytic-uremic syndrome","volume":"4","author":"Hahn","year":"1989","journal-title":"J. Child Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/BF02012739","article-title":"Hemolytic uremic syndrome: MR findings of CNS complications","volume":"24","author":"Jeong","year":"1994","journal-title":"Pediatr. Radiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s002340100557","article-title":"Brain involvement in haemolytic-uraemic syndrome: MRI features of coagulative necrosis","volume":"43","author":"Schmidt","year":"2001","journal-title":"Neuroradiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.2215\/CJN.08921209","article-title":"Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome","volume":"5","author":"Nathanson","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1093\/brain\/aws090","article-title":"The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak","volume":"135","author":"Magnus","year":"2012","journal-title":"Brain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1086\/315421","article-title":"Escherichia coli O157:H7 strains that express Shiga toxin (Stx) 2 alone are more neurotropic for gnotobiotic piglets than are isolates producing only Stx1 or both Stx1 and Stx2","volume":"181","author":"Kondova","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1177\/030098589303000502","article-title":"Clinical signs and lesions in gnotobiotic pigs inoculated with Shiga-like toxin I from Escherichia coli","volume":"30","author":"Dykstra","year":"1993","journal-title":"Vet. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Karniychuk, U.U., and Nauwynck, H.J. (2013). Pathogenesis and prevention of placental and transplacental porcine reproductive and respiratory syndrome virus infection. Vir. Res., 44.","DOI":"10.1186\/1297-9716-44-95"},{"key":"ref_47","first-page":"125","article-title":"Exogenous porcine viruses","volume":"278","author":"Paul","year":"2003","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_48","first-page":"428","article-title":"Gnotobiotic pigs-derivation and rearing","volume":"42","author":"Miniats","year":"1978","journal-title":"Can. J. Comp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1292\/jvms.10-0501","article-title":"Anesthesia of growing pigs with tiletamine-zolazepam and reversal with flumazenil","volume":"74","author":"Lee","year":"2012","journal-title":"J. Vet. Med. Sci."},{"key":"ref_50","unstructured":"AVMA Guidelines on Euthanasia, Available online: http:\/\/grants.nih.gov\/grants\/olaw\/Euthanasia2007.pdf."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/9\/2\/49\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:00Z","timestamp":1760207220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/9\/2\/49"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,26]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["toxins9020049"],"URL":"https:\/\/doi.org\/10.3390\/toxins9020049","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,26]]}}}