Development of an additive model to study the significance of heat-labile and hea

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DESCRIPTION (provided by applicant): Enterotoxigenic Escherichia coli (ETEC) associated diarrheal disease are responsible for an estimated 400,000 to 800,000 deaths annually. Bacterial adhesins or colonization factors (CFAs) and enterotoxins are the key virulence factors in ETEC diarrhea. Enterotoxins, heat-labile toxin(LT) and heat stable toxins (STa, STb) are the main enterotoxins produced by ETEC, these toxins cause disruption of fluid homeostasis and stimulate fluid secretion, which results in diarrhea. However, very limited studies have been done to study virulence significance of individual enterotoxin and to identify enterotoxin(s) of virulence determinant in ETEC diarrhea, which might directly lag vaccine development using enterotoxin(s) as antigens to prevent or decrease the severity of diarrheal disease in humans. The major obstacle to study the pathogenicity of enterotoxins is the lack of a suitable challenge model. Human subject challenge studies have been very limited because of concerns of safety risk, ethnics, and financial expanses; while rodents, the preferred models of most infectious disease research, show no susceptibility to ETEC, and therefore have little value to study ETEC disease. In contrast, certain pigs are naturally susceptible to ETEC, and K88 fimbrial ETEC pathogens to which pigs are susceptible have been studied most extensively and their correlative relationships with diarrhea are best characterized. This research proposes to clone estAB, estA, and estB genes separately for expression of LT, STa and STb, and to construct model pathogens which will allow us to examine significance of each individual enterotoxin in diarrhea. The overall goal of this project is to develop a versatile model to examine the biological relevance of individual enterotoxin in diarrhea disease. The study will elucidate the roles of LT, STa and STb in ETEC diarrhea, and determine the key enterotoxins that may pave the way for development of human ETEC vaccines based on enterotoxins as antigens.