Intestinal Physiology in the Host Response to Enteric Salmonella Infections

描述（由申请人提供）：本项目的总体目标是使用感染性结肠炎的新模型阐明沙门氏菌胃肠炎的发病机制。仅在美国，沙门氏菌肠炎估计每年影响超过100万人，成本超过14亿美元。大量的家畜和重要的农业动物也受到感染。尽管问题的严重性，但由于缺乏沙门氏菌病肠道形式的相关小鼠模型，对肠炎的发病机制知之甚少。我们最近报道了一种模拟人类感染的沙门氏菌结肠炎伴腹泻小鼠模型的开发。该模型涉及口服感染具有野生型天然抗性（Slc 11 A1或Nrammp 1）基因座并用卡那霉素预处理的小鼠。感染的小鼠发展为泛结肠炎和腹泻，伴有结肠上皮离子转运生理学的改变。该项目将涉及一项合作努力，将对沙门氏菌引起的腹泻的生理基础，细菌毒力因子的作用以及先天免疫反应途径的重要性进行整合研究。具体目标1将确定导致沙门氏菌结肠炎腹泻的病理生理机制。该方法将涉及确定上皮离子转运，屏障功能和运动性的变化对肠道疾病过程的贡献。将检验上皮损伤和细胞更新增加影响膜转运蛋白表达和功能的假设。同基因细菌毒力突变体将用于操纵疾病过程的特定阶段。具体目标2：确定宿主炎症细胞反应在沙门氏菌诱导的结肠炎和腹泻中的作用。该方法将使用抗体介导的细胞耗竭和趋化因子受体突变体来研究中性粒细胞和单核细胞浸润的作用。具体目标3：分析NF-：B在沙门氏菌感染诱导的腹泻和结肠炎中的作用。改变NF-：B活化的沙门氏菌突变体将与NF-：B活化途径中具有组织特异性缺陷的小鼠品系组合使用，以测试NF-：B信号传导减少有助于沙门氏菌肠道疾病的假设。公共卫生相关性：沙门氏菌肠炎是美国的一种常见疾病，估计每年有超过100万例。没有公认的有效治疗肠道疾病。该项目将提供详细的调查沙门氏菌肠炎的病理生理原因，并提出可能的新疗法。

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate the pathogenesis of Salmonella gastroenteritis using a new model of infectious colitis. In the US alone, Salmonella enteritis is estimated to affect over a million people per year, with costs exceeding $1.4 billion. Large numbers of domestic and agriculturally important animals are also infected. Despite the enormity of the problem, little is know about the pathogenesis of the enteritis, due to lack of a relevant mouse model for the intestinal form of Salmonella disease. We have recently reported the development of a mouse model of Salmonella colitis with diarrhea that mimics human infection. This model involves oral infection of mice possessing a wild-type natural resistance (Slc11A1 or Nrammp1) locus and pre-treated with kanamycin. Infected mice develop pan-colitis and diarrhea accompanied by alterations in colonic epithelial ion transport physiology. The project will involve a collaborative effort that will integrate studies on the physiologic basis of Salmonella-induced diarrhea, the role of bacterial virulence factors, and the importance of innate immune response pathways. Specific Aim 1 will identify the pathophysiologic mechanisms leading to diarrhea in Salmonella colitis. The approach will involve determining the contributions of changes in epithelial ion transport, barrier function, and motility to the intestinal disease process. The hypothesis that epithelial damage and increased cell turnover affects expression and function of membrane transporters will be tested. Isogenic bacterial virulence mutants will be used to manipulate specific phases of the disease process. Specific Aim 2: to determine the role of the host inflammatory cell response in Salmonella-induced colitis and diarrhea. The approach will use antibody-mediated cell depletion and chemokine receptor mutants to study the role of neutrophil and mononuclear cell infiltration. Specific Aim 3: Analysis of the role of NF-:B in diarrhea and colitis induced by Salmonella infection. Salmonella mutants that alter NF-:B activation will be used in combination with mouse strains with tissue-specific defects in the NF-:B activation pathway to test the hypothesis that decreased NF-:B signaling contributes to Salmonella intestinal disease. PUBLIC HEALTH RELEVANCE: Salmonella enteritis is a common disease in the United States with over a million cases estimated every year. There is no recognized, effective treatment for the intestinal disease. This project will provide a detailed investigation into the pathophysiologic causes of Salmonella enteritis and will suggest possible new therapies.