Intestinal Physiology in the Host Response to Enteric Salmonella Infections

宿主对肠道沙门氏菌感染反应的肠道生理学

• 批准号: 7750528
• 负责人: Donald G. Guiney
• 金额: $ 50.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750528
• 关键词: Affect; Alleles; Animals; Antibiotics; Antibodies; Biological Preservation; Body Weight decreased; Cell Culture System; Cell Death; Cells; Clinical Course of Disease; Colitis; Colon; Data; Defect; Development; Diarrhea; Disease; Electrophysiology (science); Enteral; Enterocolitis; Epithelial; Epithelial Cells; Functional disorder; Gastroenteritis; Goals; Histology; Human; Immune response; Infection; Infiltration; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Diseases; Intestinal Mucosa; Intestines; Investigation; Ion Transport; Kanamycin; Knock-out; Lead; Measurable; Mediating; Membrane Transport Proteins; Modeling; Molecular Genetics; Mononuclear; Mouse Strains; Mucous Membrane; Mus; Natural Resistance; Organ; Organism; Pathogenesis; Pathway interactions; Phase; Physiological; Physiological Processes; Physiology; Play; Process; Proteins; Reporting; Resistance; Role; Salmonella; Salmonella enterica; Salmonella infections; Signal Transduction; Signal Transduction Pathway; Stress; Structure; Systemic disease; Testing; Therapeutic Intervention; Tight Junctions; Time; Tissues; United States; Virulence; Virulence Factors; base; cell motility; chemokine receptor; cost; effective therapy; enteritis; inhibitor/antagonist; insight; macrophage; mouse model; mutant; neutrophil; novel; oral infection; pathogen; public health relevance; response; salmonella colitis

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.

描述（由申请人提供）：该项目的总体目标是利用新型感染性结肠炎模型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超过一百万人，造成的损失超过 14 亿美元。大量家养和重要农业动物也受到感染。尽管问题很严重，但由于缺乏沙门氏菌病肠道形式的相关小鼠模型，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）基因座并用卡那霉素预处理的小鼠的口腔感染。受感染的小鼠出现全结肠炎和腹泻，并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，整合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。该方法将涉及确定上皮离子转运、屏障功能和运动性变化对肠道疾病过程的影响。上皮损伤和细胞更新增加影响膜转运蛋白的表达和功能的假设将得到检验。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引起的结肠炎和腹泻中的作用。该方法将利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在沙门氏菌感染引起的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 NF-:B 激活途径中具有组织特异性缺陷的小鼠品系结合使用，以测试 NF-:B 信号传导减少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，估计每年有超过一百万例病例。对于肠道疾病，尚无公认的有效治疗方法。该项目将对沙门氏菌肠炎的病理生理原因进行详细调查，并提出可能的新疗法。