HOST DEFENSES AGAINST PATHOGENIC E. coli

宿主针对致病性大肠杆菌的防御

• 批准号: 6675249
• 负责人: LARS ECKMANN
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675249
• 关键词: B lymphocyte; Escherichia coli infections; bacterial antigens; bactericidal immunity; cellular immunity; enzyme linked immunosorbent assay; flow cytometry; gastrointestinal epithelium; gastrointestinal infection; host organism interaction; immunoglobulin A; immunoglobulin M; in situ hybridization; interleukin 6; laboratory mouse; mucosal immunity; nuclear factor kappa beta; polymerase chain reaction; secretory immune system

DESCRIPTION (provided by applicant): Pathogenic (diarrheagenic) Escherichia coli are an important cause of food-borne disease in the U.S. and developing countries. Most pathogenic E. coli strains, e.g. EPEC and EHEC, cause mucosal inflammation and disease without deep invasion into the intestinal mucosa or systemic spread. Although much progress has been made in understanding the mechanisms by which pathogenic E. coli cause disease (e.g. toxins), relatively little is known about the host defenses against these pathogens. Based on the lack of deep tissue invasion, we hypothesize that host defenses that operate in the intestinal lumen or at the mucosal surface are key for controlling and eradicating infections with most strains of pathogenic E. coil. Our preliminary data strongly support this notion since we found that B cells are absolutely required for clearance of an EPEC strain in a mouse model of infection. The proposed studies will build on this observation and define the mechanisms of B cell-dependent host defense against pathogenic E. coli, using murine infection models. We will focus specifically on the importance of secretory antibodies as immune effectors of B cells. These studies on specific immune effector mechanisms will be complemented with functional investigations on the regulation of mucosal immune defenses against pathogenic E. coli, with a particular focus on the functions of the immunoregulatory cytokine, IL-6. In addition, we will begin to determine the importance of the intestinal epithelium in orchestrating immune defenses against pathogenic E. coli, as epithelial cells are a focal point of interaction between host and most strains of pathogenic E. coll. These experiments will focus particularly on the physiologic functions of the transcription factor, NF-kappaB, in the intestinal epithelium, using a novel murine model we have developed in which a key component of the NF-kB signaling pathway is deleted selectively from intestinal epithelial cells. The proposed studies have the following Specific Aims: AIM 1. To define the mechanisms of B cell-dependent host defense against pathogenic E. coli. AIM 2. To determine the functions of IL-6 in host defense against pathogenic E. coli. AIM 3. To define the importance of epithelial cell NF-kappaB in host defense against pathogenic E. coll. Together, these studies will provide significant new insights into the key host defenses by which the host can eradicate infection with pathogenic E. coli, thus providing an important basis for designing immunization strategies against these pathogens.

描述（由申请方提供）：致病性（产肠源性）大肠杆菌是美国和发展中国家食源性疾病的重要原因。致病性最强的E.大肠杆菌菌株，例如EPEC和EHEC，引起粘膜炎症和疾病，而不深入侵入肠粘膜或全身扩散。虽然在致病性大肠杆菌的致病机制方面已经取得了很大进展。大肠杆菌引起的疾病（如毒素），对宿主防御这些病原体的了解相对较少。基于缺乏深部组织侵袭，我们假设在肠腔或粘膜表面操作的宿主防御是控制和根除大多数致病性E.线圈 我们的初步数据强烈支持这一观点，因为我们发现B细胞是清除小鼠感染模型中EPEC菌株所绝对需要的。拟议的研究将建立在这一观察结果的基础上，并定义B细胞依赖性宿主防御病原性大肠杆菌的机制。coli，使用鼠感染模型。我们将特别关注分泌性抗体作为B细胞免疫效应子的重要性。这些关于特异性免疫效应机制的研究将与关于粘膜免疫防御对致病性大肠杆菌的调节的功能研究相补充。大肠杆菌，特别关注免疫调节细胞因子IL-6的功能。此外，我们将开始确定肠上皮在协调免疫防御致病性大肠杆菌中的重要性。大肠杆菌，因为上皮细胞是宿主与大多数致病性大肠杆菌菌株之间相互作用的焦点。这些实验将特别关注转录因子NF-κ B在肠上皮中的生理功能，使用我们开发的新的小鼠模型，其中NF-κ B信号通路的关键组分从肠上皮细胞中选择性地缺失。拟议的研究有以下具体目标：目的1。目的探讨B细胞依赖的宿主防御致病性大肠杆菌的机制。杆菌AIM 2.探讨IL-6在宿主防御致病性大肠杆菌中的作用。杆菌AIM 3.目的探讨上皮细胞NF-κ B在宿主防御致病性大肠杆菌中的作用。总之，这些研究将为宿主根除致病性大肠杆菌感染的关键宿主防御提供重要的新见解。大肠杆菌，从而为设计针对这些病原体的免疫策略提供了重要依据。