Intestinal Physiology in the Host Response to Enteric Salmonella Infections

描述(由申请人提供)：这个项目的总体目标是利用一种新的感染性结肠炎模型来阐明沙门氏菌胃肠炎的发病机制。据估计，仅在美国，沙门氏菌肠炎每年就会影响100多万人，造成的损失超过14亿美元。大量家养和农业上重要的动物也被感染。尽管问题很严重，但由于缺乏与沙门氏菌肠道形式相关的小鼠模型，人们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腹泻小鼠模型的开发。该模型涉及具有野生型自然抗性(SLc11A1或Nrammp1)基因座并经卡那霉素预处理的小鼠的口腔感染。感染的小鼠会出现泛结肠炎和腹泻，并伴有结肠上皮离子转运生理的改变。该项目将涉及一项合作努力，将整合关于沙门氏菌引起腹泻的生理学基础、细菌毒力因子的作用以及先天免疫反应途径的重要性的研究。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。该方法将包括确定上皮细胞离子转运、屏障功能和动力变化对肠道疾病过程的贡献。上皮损伤和细胞周转增加会影响膜转运蛋白的表达和功能的假设将得到验证。同基因细菌毒力突变将被用来操纵疾病过程的特定阶段。具体目的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来研究中性粒细胞和单核细胞渗透的作用。具体目标3：分析核因子-B在沙门氏菌感染所致腹泻和结肠炎中的作用。改变NF-：B激活的沙门氏菌突变体将与在NF-：B激活途径中存在组织特异性缺陷的小鼠品系结合使用，以检验NF-：B信号减弱导致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100多万病例。目前还没有公认的有效的肠道疾病治疗方法。这个项目将对沙门氏菌肠炎的病理生理原因进行详细的调查，并将提出可能的新疗法。

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.