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.
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