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: 8415536
• 负责人: Donald G. Guiney
• 金额: $ 46.93万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415536
• 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; Health; Histology; Human; Immune response; Infection; Infiltration; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Diseases; Intestinal Mucosa; Intestines; Investigation; Ion Channel; 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; 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.

描述（由申请人提供）：该项目的总体目标是使用新的感染性结肠炎模型阐明沙门氏菌胃肠炎的发病机理。仅在美国，沙门氏菌肠炎估计每年会影响超过100万人，费用超过14亿美元。还感染了大量的家庭和农业重要动物。尽管问题很大，但由于缺乏与沙门氏菌疾病的肠道形式相关的小鼠模型，对肠炎的发病机理知之甚少。我们最近报道了一种模仿人类感染的腹泻的沙门氏菌结肠炎小鼠模型。该模型涉及具有野生型自然抗性（SLC11A1或NRAMMP1）且用卡纳米霉素预处理的小鼠口腔感染。感染的小鼠患有泛神炎和腹泻，并伴有结肠上皮离子转运生理学的改变。该项目将涉及一项协作努力，该努力将基于沙门氏菌诱导的腹泻的生理基础，细菌毒力因子的作用以及先天免疫反应途径的重要性整合研究。具体目标1将确定导致沙门氏菌炎腹泻的病理生理机制。该方法将涉及确定上皮离子转运，屏障功能和运动对肠道疾病过程的贡献。将测试上皮损伤和增加细胞更新会影响膜转运蛋白的表达和功能的假设。等生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。特定目的3：分析沙门氏菌感染引起的NF-：B在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激活途径中组织特异性缺陷的小鼠菌株结合使用，以测试降低NF-：B信号传导的假设有助于沙门氏菌肠道疾病。