Host Interactions of Salmonella typhimurium

描述（由申请人提供）：沙门氏菌引起的肠胃炎是美国与病毒、寄生虫或细菌相关的食源性疾病中最常见的死亡原因。我们的长期目标是阐明肠炎沙门氏菌血清型鼠伤寒引起的肠胃炎的分子机制。本应用程序的目的是研究参与启动炎症反应的细菌因素，并表征有助于遏制这种侵袭性病原体的效应机制。我们的中心假设是，初始反应触发局部白细胞介素IL-17扩增环，导致中性粒细胞募集和防御素产生。我们将测试我们假设的不同方面，并通过追求以下具体目标来实现本应用程序的目标：诱导阶段：确定启动宿主反应的机制。我们将在小腿模型中测试模式识别参与启动炎症反应的工作假设。2. 效应期：明确上皮细胞诱导效应功能的分子通路。我们将测试IL-17旁分泌信号通过诱导肠上皮中CXC趋化因子和防御素的表达来驱动双管齐下的先天免疫反应的工作假设。这项提议的工作具有创新性，因为它使用了一种新的动物模型——小牛来研究肠胃炎。我们期望我们的方法将确定导致胃肠炎期间中性粒细胞内流的关键事件。这一结果将具有重要意义，因为它将为肠道炎症的基本机制提供见解。

DESCRIPTION (provided by applicant): 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.