Host Interactions of Salmonella typhimurium

描述（由申请方提供）：沙门氏菌诱导的胃肠炎是美国与病毒、寄生虫或细菌相关的食源性疾病导致死亡的最常见原因。我们的长期目标是阐明S.肠道血清型伤寒沙门氏菌引起的胃肠炎。本申请的目的是研究参与启动炎症反应的细菌因子，并表征有助于遏制这种侵入性病原体的效应机制。我们的中心假设是，启动响应触发局部白细胞介素IL-17放大环，这导致中性粒细胞募集和防御素的生产。我们将测试我们的假设的不同方面，并通过追求以下具体目标来实现本申请的目标：1.诱导阶段：确定宿主反应启动的机制。我们将测试工作假设，即模式识别参与启动小牛模型中的炎症反应。2.效应阶段：确定上皮细胞诱导效应功能的分子途径。我们将测试的工作假设，IL-17旁分泌信号驱动一个双管齐下的先天性免疫反应，诱导表达在肠上皮细胞的CXC趋化因子和防御素。这项工作是创新的，因为它使用了一种新的动物模型，小牛，来研究胃肠炎。我们期望我们的方法将确定胃肠炎期间导致中性粒细胞流入的关键事件。这一结果将是有意义的，因为它将提供深入了解肠道炎症的基本机制。公共卫生相关性：小鼠是研究病原体和不同细胞类型在体内复杂的相互作用的有吸引力的模式生物，但在这个物种中观察到的先天宿主反应并不总是准确地复制那些在人类肠粘膜。因此，导致人类肠道炎症的一些基本机制仍然知之甚少。我们已经组建了一个由准备充分的研究人员组成的研究小组，他们提出通过采用一种新的动物模型（牛宿主）来填补这一知识空白，该动物模型在临床表现、病理变化和在S.鼠伤寒感染。

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. PUBLIC HEALTH RELEVANCE: 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.