Diarrheagenic E. coli/HUS

Diarrheagenic E. coli

Numerous enteric diseases are caused by various forms of diarrheagenic E. coli, including: enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC) and enteroaggregative E. coli (EAEC). These related pathogens each cause mild to severe diarrhea in most all countries, with their greatest prevalence and impact in the developing world. More information on these diseases is available at the CDC website. The Department of Infectious Diseases has ongoing research on several of these pathogens, including pioneering work developing gnotobiotic pig models, with the major focus on EHEC.

EHEC/HUS

E. coli O157 and related bacteria are responsible for 100,000 infections in the United States annually. People contract the bacteria by eating undercooked meat or by drinking contaminated liquids like milk. While infection can cause bloody diarrhea in adults, in five to 15 percent of children and the elderly it can lead to kidney disease and kidney failure, a condition known as hemolytic uremic syndrome (HUS). This syndrome is the single most important cause of acute kidney failure in children in the US and other developed countries. HUS can lead to death in some cases, and surviving patients often sustain serious kidney damage requiring dialysis or kidney transplantation. The Department of Infectious Disease and Global Health has recently developed a human monoclonal antibody therapy for HUS that we expect to test for efficacy in human clinical trials. We are also advancing development of single-domain antibodies (sdAbs) derived from alpacas, called VHHs, that target and neutralize the Shiga toxins Stx1 and Stx2 produced by EHEC. The VHHs are engineered into heteromultimers resulting in potent antitoxin VHH-based neutralizing agents (VNAs) that have demonstrated efficacy in mouse and pig models of EHEC when administered as proteins or by gene therapy. More details on VNAs are available at the Novel Antitoxin Agents webpage.

Publications

Sheoran AS, Dmitriev IP, Kashentseva EA, Cohen O, Mukherjee J, Debatis M, Shearer J, Tremblay JM, Beamer G, Curiel DT, Shoemaker CB, Tzipori S.. 2014. Adenovirus vector expressing Stx1/2-neutralizing agent protects piglets infected with E. coli O157:H7 against fatal systemic intoxication. Infect Immun. 83:286-91. PMCID: PMC4288880
Tremblay JM, Mukherjee J, Leysath CE, Debatis M, Ofori K, Baldwin K, Boucher C, Peters R, Beamer G, Sheoran A, Bedenice D, Tzipori S, Shoemaker CB. 2013. A single VHH-based toxin neutralizing agent and an effector antibody protects mice against challenge with Shiga toxins 1 and 2. Infect Immun. Dec;81(12):4592-603. doi: 10.1128/IAI.01033-13. Epub 2013 Sep 30. PMCID: PMC3837998
Sheoran A, Jeong KI, Mukherjee J, Wiffin A, Singh P, Tzipori S. 2012. Biodistribution and elimination kinetics of systemic Stx2 by the Stx2A and Stx2B subunit-specific human monoclonal antibodies in mice. BMC Immunol. 13:27. PMID: 22655967
Pieper R, Zhang Q, Clark DJ, Huang ST, Suh MJ, Braisted JC, Payne SH, Fleischmann RD, Peterson SN, Tzipori S. 2011. Characterizing the Escherichia coli O157:H7 proteome including protein associations with higher order assemblies. PLoS One. 6:e26554. PMID: 22087229
Jeong KI, Chapman-Bonofiglio S, Singh P, Lee J, Tzipori S, Sheoran AS. 2010. In vitro and in vivo protective efficacies of antibodies that neutralize the RNA N-glycosidase activity of Shiga toxin 2. BMC Immunol. 11:16. PMID: 20334660
Jeong KI, Tzipori S, Sheoran AS. 2010. Shiga toxin 2-specific but not shiga toxin 1-specific human monoclonal antibody protects piglets challenged with enterohemorrhagic Escherichia coli producing shiga toxin 1 and shiga toxin 2. J Infect Dis. 201:1081-3. PMID: 20196656
Jeong KI, Zhang Q, Nunnari J, Tzipori S. 2010. A piglet model of acute gastroenteritis induced by Shigella dysenteriae Type 1. J Infect Dis. 201:903-11. PMID:20136414
Akiyoshi DE, Sheoran AS, Rich CM, Richard L, Chapman-Bonofiglio S, Tzipori S. 2010. Evaluation of Fab and F(ab’)2 fragments and isotype variants of a recombinant human monoclonal antibody against Shiga toxin 2. Infect Immun. 78:1376-82. PMID:20086088
Zhang Q, Donohue-Rolfe A, Krautz-Peterson G, Sevo M, Parry N, Abeijon C, Tzipori S. 2009. Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J Infect Dis. 199:486-93. PMID:19125676
Krautz-Peterson G, Chapman-Bonofiglio S, Boisvert K, Feng H, Herman IM, Tzipori S, Sheoran AS. 2008. Intracellular neutralization of shiga toxin 2 by an a subunit-specific human monoclonal antibody. Infect Immun. 76:1931-9. PMID:18285498
Sheoran AS, Chapman-Bonofiglio S, Harvey BR, Mukherjee J, Georgiou G, Donohue-Rolfe A, Tzipori S. 2005. Human antibody against shiga toxin 2 administered to piglets after the onset of diarrhea due to Escherichia coli O157:H7 prevents fatal systemic complications. Infect Immun. 73:4607-13. PMID:16040972
Akiyoshi DE, Rich CM, O’Sullivan-Murphy S, Richard L, Dilo J, Donohue-Rolfe A, Sheoran AS, Chapman-Bonofiglio S, Tzipori S. 2005. Characterization of a human monoclonal antibody against Shiga toxin 2 expressed in Chinese hamster ovary cells. Infect Immun. 73:4054-61. PMID:15972493
Tzipori S, Sheoran A, Akiyoshi D, Donohue-Rolfe A, Trachtman H. 2004. Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev. 17:926-41. PMID:15489355
Sheoran AS, Chapman S, Singh P, Donohue-Rolfe A, Tzipori S. 2003. Stx2-specific human monoclonal antibodies protect mice against lethal infection with Escherichia coli expressing Stx2 variants. Infect Immun. 71:3125-30. PMID:12761090
Mukherjee J, Chios K, Fishwild D, Hudson D, O’Donnell S, Rich SM, Donohue-Rolfe A, Tzipori S. 2002. Production and characterization of protective human antibodies against Shiga toxin 1. Infect Immun. 70:5896-9. PMID:12228326
Mukherjee J, Chios K, Fishwild D, Hudson D, O’Donnell S, Rich SM, Donohue-Rolfe A, Tzipori S. 2002. Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection. Infect Immun. 70:612-9. PMID: 11796590
Donohue-Rolfe A, Kondova I, Oswald S, Hutto D, Tzipori S. 2000. Escherichia coli O157:H7 strains that express Shiga toxin (Stx) 2 alone are more neurotropic for gnotobiotic piglets than are isotypes producing only Stx1 or both Stx1 and Stx2. J Infect Dis. 181:1825-9. PMID:10823794
Donohue-Rolfe A, Kondova I, Mukherjee J, Chios K, Hutto D, Tzipori S. 1999. Antibody-based protection of gnotobiotic piglets infected with Escherichia coli O157:H7 against systemic complications associated with Shiga toxin 2. Infect Immun. 67(7):3645-8. PMID:10377152
Gunzer F, Bohn U, Fuchs S, Mühldorfer I, Hacker J, Tzipori S, Donohue-Rolfe A. 1998. Construction and characterization of an isogenic slt-ii deletion mutant of enterohemorrhagic Escherichia coli. Infect Immun. 66:2337-41. PMID:9573126
Tzipori S, Gunzer F, Donnenberg MS, de Montigny L, Kaper JB, Donohue-Rolfe A. 1995. The role of the eaeA gene in diarrhea and neurological complications in a gnotobiotic piglet model of enterohemorrhagic Escherichia coli infection. Infect Immun. 63:3621-7. PMID:7642299