NEUROENDOCRINE MEDIATION OF E. COLI 0157:H7 INFECTION

这项应用提出了定向神经内分泌-细菌相互作用的新理论，作为一种控制肠道病原体感染宿主能力的机制。这一假说是基于神经内分泌激素去甲肾上腺素(NE)在体外和体内促进肠道病原体O157：H7的生长和产生毒力相关因子的能力。被大肠杆菌O157：H7污染的食物中存在高浓度的去甲肾上腺素，如碎牛肉。由于肠道神经系统的活动，胃肠道中也存在同样高浓度的去甲肾上腺素。因此，拟议的研究将检查从富含NE的食物受到E.ColiO157：H7污染到肠道内感染期间NE的存在是否可能是导致出血性结肠炎的一个因素。本实验室的结果表明，NE对大肠杆菌O157：H7污染富含NE的食物引起肠道内感染的影响可能是介导出血性结肠炎发生的一个因素。本实验室的结果表明，去甲肾上腺素对O157：H7大肠杆菌的影响是由于产生了一种自动生长诱导剂。因此，我们的具体目标是：1)确定补充了在常见污染食物中发现的NE水平的纯净饮食对胃肠系统内富含NE的环境中的大肠杆菌O157：H7的能力；2)检测从应激和非应激小鼠的胃肠道Trat分离的E.ColiO157：H7的能力，因为应激和对照动物之间NE管腔水平的差异将提供更多关于应激改变结肠炎易感性的公认能力的理解；4)测定小鼠对添加去甲肾上腺素(NE)的饮食对照O157：H7的应激反应能力；5)检测阻断胃肠道内NE释放是否能改变对E.ColiP157：H7的应激敏感性；6)纯化NE诱导的O157：H7自身生长诱导物的血清结合型，并确定其结构，为开发特异性阻断细菌分裂的药物以及鉴定参与其生产的基因(S)提供基础。总而言之，上述目标旨在建立食物中NE含量与胃肠道Trat之间的直接因果关系，以影响大肠杆菌O157：H7导致感染的能力。证实直接神经内分泌-细菌相互作用是大肠杆菌O157：H7感染的发病机制，可能为出血性结肠炎的预防和治疗提供新的治疗方法。

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.