Salmonella serotypes are the leading cause of food-borne infections with lethal outcome in the United States. The pathogenesis of this diarrheal disease has not been intensively studied in Salmonella since diarrhea does not develop in rodent models. In contrast, calves infected with S. Typhimurium develop similar signs of disease and pathology as observed in humans. Our long-range goal is to elucidate the molecular mechanisms involved in the pathogenesis of S. Typhimurium-induced enterocolitis. The objectives of this application are to study how the invasion associated type III secretion system (TTSS-1) of S. Typhimurium directs migration of neutrophils into the intestinal mucosa and to determine the role of neutrophils in causing fluid accumulation and intestinal pathology in the calf. Our central hypothesis is that upregulation of CXC chemokines in the bovine intestinal mucosa induced by TTSS-1 secreted effector proteins elicits a neutrophil influx, which is the main mechanism leading to tissue injury and diarrhea during S. Typhimurium-induced enterocolitis. The rationale for the proposed research is that a better understanding of the complex series of events leading to inflammation and fluid accumulation during the interaction of S. Typhimurium with host tissue in vivo will be required for the development of new and innovative approaches for treatment and prevention. We will test different aspects of our hypothesis by pursuing the following four specific aims: (1) Determine the role of TTSS-1 in inducing the production of CXC chemokines in the intestinal mucosa; (2) Investigate CXC chemokine expression in bovine tissue on the cellular level; (3) Determine the contribution of CXC chemokines to neutrophil recruitment during S. Typhimurium induced enterocolitis; (4) Determine the role of neutrophils in S. Typhimurium induced fluid accumulation. We are particularly well prepared to perform the proposed studies because we have established the calf model of human enterocolitis and have identified S. Typhimurium virulence factors, which are essential for causing this disease syndrome. It is our expectation that our approach will establish the complex series of events leading to fluid accumulation during enterocolitis. This outcome will be significant because identification of the key events during S Typhimurium interaction with host tissue in vivo will have a considerable impact on the design of in vitro models used by other investigators in the field.
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