The principal cause of HUS is Escherichia coli which produce verotoxin, e.g., Shiga-like toxin (SLT). Prior to the onset of HUS, SLT producing E.coli (SLTEC) colonize the intestine and produce SLT which is then absorbed systemically and binds to specific receptors in renal glomeruli causing vascular damage leading to kidney failure and HUS. It is thought that cytokines such as tumor neurosis factor (TNF) predispose to and enhance the vascular damage. This research will utilize a naturally occurring animal model of systemic SLT induced vascular damage (edema disease of swine) to define early (pre-clinical, pre-renal, and pre-vascular) stages in the pathogenesis of SLTEC infections. Specifically, the research will define the times from infection to SLT production, from SLT production to its appearance in blood, to increased TNF production, to initial vascular damage and to the first signs of clinical disease. It will determine if antibodies against SLT can induce protection when given after SLT is produced, but before it is absorbed, or if given at the time SLT is first detectable in blood, or at the time of the first clinical signs. It will determine if tests for the concentration of SLT in blood or intestine have predictive value as to the severity of the resulting vascular damage and clinical disease. The work will determine if programmed cell death is a mechanism of vascular damage. The knowledge gained will be useful in developing rational strategies for the prevention of HUS by detection of and intervention in SLTEC infection before SLT becomes systemic, binds to glomerular capillaries or causes irreversible vascular damage. Field trials, utilizing an antitoxin vaccine, will be conducted to determine if SLTEC infection causes low level vascular damage and impaired growth (subclinical disease) in animals that become infected, but do not develop clinical disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041328-04
Application #
2887444
Study Section
Special Emphasis Panel (SRC (01))
Project Start
1996-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Ames
State
IA
Country
United States
Zip Code
50011
Matise, Ilze; Cornick, Nancy A; Samuel, James E et al. (2003) Binding of shiga toxin 2e to porcine erythrocytes in vivo and in vitro. Infect Immun 71:5194-201
Cornick, Nancy A; Booher, Sheridan L; Moon, Harley W (2002) Intimin facilitates colonization by Escherichia coli O157:H7 in adult ruminants. Infect Immun 70:2704-7
Booher, S L; Cornick, N A; Moon, H W (2002) Persistence of Escherichia coli O157:H7 in experimentally infected swine. Vet Microbiol 89:69-81
Matise, I; Cornick, N A; Booher, S L et al. (2001) Intervention with Shiga toxin (Stx) antibody after infection by Stx-producing Escherichia coli. J Infect Dis 183:347-350
Matise, I; Sirinarumitr, T; Bosworth, B T et al. (2000) Vascular ultrastructure and DNA fragmentation in swine infected with Shiga toxin-producing Escherichia coli. Vet Pathol 37:318-27
Cornick, N A; Booher, S L; Casey, T A et al. (2000) Persistent colonization of sheep by Escherichia coli O157:H7 and other E. coli pathotypes. Appl Environ Microbiol 66:4926-34
Pruimboom-Brees, I M; Morgan, T W; Ackermann, M R et al. (2000) Cattle lack vascular receptors for Escherichia coli O157:H7 Shiga toxins. Proc Natl Acad Sci U S A 97:10325-9
Dean-Nystrom, E A; Pohlenz, J F; Moon, H W et al. (2000) Escherichia coli O157:H7 causes more-severe systemic disease in suckling piglets than in colostrum-deprived neonatal piglets. Infect Immun 68:2356-8
Cornick, N A; Matise, I; Samuel, J E et al. (2000) Shiga toxin-producing Escherichia coli infection: temporal and quantitative relationships among colonization, toxin production, and systemic disease. J Infect Dis 181:242-51
Moon, H W; Hoffman, L J; Cornick, N A et al. (1999) Prevalences of some virulence genes among Escherichia coli isolates from swine presented to a diagnostic laboratory in Iowa. J Vet Diagn Invest 11:557-60

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