Immunomodulation in infectious diarrhea

感染性腹泻的免疫调节

• 批准号: 7095912
• 负责人: JAN-MICHAEL AXEL KLAPPROTH
• 金额: $ 12.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095912
• 关键词: Clostridium; Escherichia coli; T cell receptor; T lymphocyte; bacterial toxins; clinical research; diarrhea; gastrointestinal infection; gene mutation; genetically modified animals; glycosyltransferase; guanine nucleotide binding protein; human subject; immunosuppression; interferon gamma; interleukin 2; interleukin 4; laboratory mouse; leukocyte activation /transformation; mucosal immunity; site directed mutagenesis

DESCRIPTION (provided by applicant): The goal of the principal investigator is to continue to develop intellectual, technical, and analytical skills to become an independently funded physician-scientist investigator in microbial pathogenesis, examining the effect of bacterial products on the immune system. The program to achieve this goal will consist of additional didactic and laboratory training in basic immunology, lymphocyte signal transduction, and microbial and molecular genetics. Bacterial immunomodulatory products are of utmost importance in infectious diseases and their prevention. For example, C. difficile toxin A and B are implicated in the development of pseudomembranous enterocolitis, and cholera toxin functions as an adjuvant in oral immunization. In this proposal we will continue to characterize a novel toxin from Enteropathogenic E. coli (EPEC), resulting in marked inhibition of T cell activation. The inhibitory gene, lifA (lymphocyte inhibitory activity), encodes for a protein with the putative size of 366kDa. The lifA gene product, lymphostatin, bears significant similarity to the N-terminus of large Clostridial cytotoxins, encoding for a glucosyltransferase motif, which is critical for their specific activity. Similar immunosuppressive genes and biological activity have been identified in related bacteria, including other EPEC strains, Enterohemorrhagic E. coli, and the mouse pathogen C. rodentium. Our hypothesis is that the glucosyltransferase motif in lymphostatin is critical for the observed immunosuppression, leading to inhibition of defined lymphocyte subpopulations of the adaptive immune response and allowing firm establishment of enteric Gram negative infection. To test the hypothesis, we propose: Aim 1: To identify the co-substrate and target molecule(s) in lymphocytes exposed to lymphostatin. Aim 2: To investigate intracellular activation pathways in defined lymphocyte populations affected by lymphostatin, resulting in suppression of IL-2, IL-4, and IFN-gamma expression. Aim 3: To investigate whether lymphostatin suppresses the mucosal adaptive immune response and firmly establishes C. rodentium enteric infection in vivo. The proposed research project will contribute to the understanding of immune mechanisms involved in the pathogenesis of chronic infectious diarrhea and gastrointestinal inflammation as seen in Crohn's disease and ulcerative colitis.

描述（由申请人提供）： 首席研究者的目标是继续发展智力，技术和分析能力，成为微生物发病机理中独立资助的医师科学家研究者，研究细菌产物对免疫系统的影响。实现此目标的程序将包括基本免疫学，淋巴细胞信号转导以及微生物和分子遗传学的其他教学和实验室训练。 细菌免疫调节产品在传染病及其预防中至关重要。 例如，艰难梭菌毒素A和B与假膜小肠结肠炎的发展有关，霍乱毒素在口服免疫中起作用。 在此提案中，我们将继续表征来自肠病大肠杆菌（EPEC）的新型毒素，从而显着抑制T细胞活化。抑制性基因LIFA（淋巴细胞抑制活性）编码定义大小为366KDA的蛋白质。 LIFA基因产物淋巴结蛋白与大型梭菌细胞毒素的N末端具有显着相似性，该N末端编码葡萄糖基转移酶基序，这对于其特定活性至关重要。在相关细菌中已经鉴定出类似的免疫抑制基因和生物学活性，包括其他EPEC菌株，肠ha骨大肠杆菌和小鼠病原体。 我们的假设是，淋巴结蛋白中的葡萄糖基转移酶基序对于观察到的免疫抑制至关重要，从而抑制了适应性免疫反应的确定淋巴细胞亚群，并允许企业建立肠肠上的阴性阴性感染。为了检验假设，我们提出：目标1：鉴定暴露于淋巴结蛋白的淋巴细胞中的co-基底和靶分子。目标2：研究受淋巴结蛋白影响的定义淋巴细胞群体中的细胞内激活途径，从而导致IL-2，IL-4和IFN-GAMMA表达抑制。目的3：研究淋巴结蛋白是否抑制粘膜适应性免疫反应并牢固地在体内建立啮齿动物肠of肠感染。 拟议的研究项目将有助于理解慢性感染性腹泻和胃肠道炎症的发病机理，如克罗恩病和溃疡性结肠炎所见。