Salmonella-induced gastroenteritis is the single most common cause of death from food-borne illnesses associated with viruses, parasites or bacteria in the US. Our long-range goal is to elucidate the molecular mechanisms of S. enterica serotype Typhimurium-induced gastroenteritis. The objectives of this application are to study the bacterial factors involved in initiating inflammatory responses and characterize effector mechanisms that help to contain this invasive pathogen. Our central hypothesis is that initiating responses trigger a local interleukin IL-17 amplification loop, which leads to neutrophil recruitment and defensin production. We will test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following specific aims: 1. Induction phase: Determine the mechanisms involved in the initiation of host responses. We will test the working hypothesis that pattern recognition is involved in initiating inflammatory responses in the calf model. 2. Effector phase: Define the molecular pathways of inducible effector function of epithelial cells. We will test the working hypothesis that IL-17 paracrine signaling drives a two-pronged innate immune response by inducing expression in the intestinal epithelium of both CXC chemokines and defensins. The proposed work is innovative because it uses a new animal model, the calf, to study gastroenteritis. It is our expectation that our approach will establish key events leading to neutrophil influx during gastroenteritis. This outcome will be significant because it will provide insights into basic mechanism of intestinal inflammation.
Mice are attractive model organisms for studying the complex series of interactions between pathogens and different cell types in vivo, but innate host responses observed in this species do not always reproduce accurately those in the human intestinal mucosa. As a result, some of the fundamental mechanisms leading to intestinal inflammation in humans have remained poorly understood. We have assembled a research team of well-prepared investigators who propose to fill this gap in knowledge by employing a new animal model, the bovine host, which closely resembles the human with regard to clinical manifestations, pathological changes and changes in host gene expression observed during S. Typhimurium infection.
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