NEUROENDOCRINE MEDIATION OF E. COLI 0157:H7 INFECTION

大肠杆菌 0157:H7 感染的神经内分泌调节

• 批准号: 6130402
• 负责人: MARK LYTE
• 金额: $ 18.59万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6130402
• 关键词: Escherichia coli 0157:H7; bacteria infection mechanism; gastrointestinal infection; laboratory mouse; microorganism growth; neuroendocrine system; norepinephrine; physiologic stressor; virulence

This application proposes the new theory of directed neuroendocrine- bacterial interactions as a mechanism governing the ability of an enteric pathogen to infect a host. This hypothesis is based on the in vitro and in vivo ability of the neuro-endocrine hormone norepinephrine (NE) to increase growth and production of virulence-associated factors of the enteric pathogen Escherichia coli O157:H7. High concentration of NE occur in foods such as ground beef which are contaminated by E. coli O157:H7. Equally high concentrations of NE also occur within the gastrointestinal tract due to enteric nervous system activity. The proposed research will therefore examine whether the presence of NE from the time of E. coli O157:H7 contamination of NE-rich foods to infection within the gut may be a factor mediating the development of hemorrhagic colitis. Results from this laboratory have shown that the effect of NE on E. coli O157:H7 contamination of NE-rich foods to infection within the gut may be a factor mediating the development of hemorrhagic colitis. Results from this laboratory have shown that the effect of NE on E. coli O157: H7 is due to the production of an autoinducer of growth. Thus, our Specific Aims are: 1) To determine the ability of a purified diet supplemented with levels of NE found in commonly contaminated foods to "prime" E. coli O157:H7 for the NE-rich environment within the gastrointestinal system; 2) To examine the ability of E. coli O157:H7 isolated from gastrointestinal trat of stressed and non-stressed mice since differences in luminal levels of NE between stressed and control animals would provide greater understanding of the recognized ability of stress to alter susceptibility to colitis; 4) To determine the ability of stress of alter the susceptibility of mice to oral challenge with E. coli O157:H7 exposed in vitro to control of NE supplemented diets; 5) To examine whether blockage of NE release within the gastrointestinal tract can alter susceptibility to challenge with E. coli P157:H7; and 6) To purify the serum-bound form of the NE-induced E. coli O157:H7 autoinducer of growth and determine its structure which may provide the basis for the development of agents to specifically interrupt bacterial division as well as identify the gene(s) involved in its production. Collectively, the above aims will seek to establish a direct cause and effect relationship between the NE content within food and the gastrointestinal trat to influence the ability of E. coli O157:H7 to cause infection. The demonstration of direct neuroendocrine-bacterial interaction as a mechanism in the pathogenesis of E. coli O157:H7 infection may yield new treatments for both the prevention and treatment of hemorrhagic colitis.

这一应用提出了定向神经内分泌-细菌相互作用作为控制肠道病原体感染宿主能力的机制的新理论。这一假设是基于神经内分泌激素去甲肾上腺素（NE）在体外和体内能够促进肠道病原体大肠杆菌O157:H7的生长和毒力相关因子的产生。高浓度的NE出现在被大肠杆菌O157:H7污染的碎牛肉等食物中。由于肠道神经系统的活动，胃肠道内也会出现同样高浓度的NE。因此，拟议的研究将检查从富含NE的食物被大肠杆菌O157:H7污染到肠道内感染的NE的存在是否可能是介导出血性结肠炎发展的一个因素。该实验室的结果表明，NE对富含NE的食物污染的大肠杆菌O157:H7对肠道感染的影响可能是介导出血性结肠炎发展的一个因素。该实验室的结果表明，NE对大肠杆菌O157: H7的作用是由于产生了一种生长的自诱导剂。因此，我们的具体目标是：1)确定在通常被污染的食物中添加NE水平的纯化饮食对胃肠道系统内富含NE的环境中大肠杆菌O157:H7的“启动”能力；2)检测从应激和非应激小鼠胃肠道中分离的大肠杆菌O157:H7的能力，因为应激和对照动物肠道内NE水平的差异将有助于更好地了解应激改变结肠炎易感性的能力；4)确定应激改变小鼠对体外暴露的大肠杆菌O157:H7口腔攻击的敏感性的能力，以控制NE补充的饮食；5)观察阻断胃肠道内NE释放是否能改变大肠杆菌P157:H7侵袭的易感性；6)纯化ne诱导的大肠杆菌O157:H7生长自诱导物的血清结合形式，确定其结构，为开发特异性阻断细菌分裂的药物以及鉴定其产生的相关基因提供依据。综上所述，上述目标将寻求建立食物中NE含量与胃肠道特性之间的直接因果关系，从而影响大肠杆菌O157:H7引起感染的能力。在大肠杆菌O157:H7感染的发病机制中，神经内分泌-细菌直接相互作用的证明可能为预防和治疗出血性结肠炎提供新的治疗方法。