Host Cell Killing by EPEC: Central Role in Pathogenesis

EPEC 杀死宿主细胞：发病机制中的核心作用

• 批准号: 6573597
• 负责人: John K. Crane
• 金额: $ 9.16万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573597
• 关键词: Escherichia coli; adenine nucleotides; adenosine; adenosine triphosphate; apoptosis; bacteria infection mechanism; biological signal transduction; chloride channels; cyclic AMP; cytoskeleton; diarrhea; gastrointestinal epithelium; host organism interaction; laboratory rabbit; pathologic process

DESCRIPTION (provided by applicant): Enteropathogenic E. coli (EPEC) is a common cause of severe, watery diarrhea in children in developing countries. EPEC is also the prototype of a group of attaching and effacing intestinal pathogens, including enterohemorrhagic E. coli (EHEC, such as O157:H7), Citrobacter rodentium, Hafnia alvei, and EPEC-like E. coli strains of domestic animals. Unlike many other E. coli strains that cause diarrhea, EPEC produces no known toxins, so the way it causes disease has been puzzling. Despite major advances in understanding how EPEC adhere, trigger cytoskeletal rearrangements in the host, and cause other host cell alterations, the mechanism by which EPEC causes diarrhea has been unclear. The discovery that EPEC triggers host cell death provided an important lead in how EPEC causes disease. The mode of cell death triggered by EPEC has features of both apoptosis (programmed cell death) and necrosis. One of the non-apoptotic features of EPEC-mediated killing is release of adenosine triphosphate (ATP) from the host cell. Once released, ATP is broken down to other adenine nucleotides and adenosine. Adenosine itself acts as a potent secretatagogue, i.e., a stimulator of intestinal fluid and electrolyte secretion, which may cause or contribute to watery diarrhea. The present application seeks to understand how EPEC triggers the ATP release from the host, with a particular focus on the role of the cystic fibrosis transmembrane regulator (CFTR). Other goals include determining the signaling pathways activated by adenosine which activate intestinal secretion, and the determining the extent of release of adenine nucleotides into the intestinal tract of rabbits infected with the EPEC-like pathogens rabbit diarrheagenic E. coli (RDEC-1) and rabbit EPEC (REPEC).

描述（由申请人提供）：肠病大肠杆菌（EPEC）是发展中国家儿童严重，水性腹泻的常见原因。 EPEC也是一组附着和脱发的肠道病原体的原型，包括肠ha虫大肠杆菌（EHEC，例如O157：H7），柠檬酸杆菌，hafnia alvei和epec类的家谱大肠杆菌菌株。与许多其他引起腹泻的大肠杆菌菌株不同，EPEC不会产生已知的毒素，因此引起疾病一直令人困惑的方式。尽管在了解EPEC粘附的方式方面取得了重大进展，但诱导宿主中的细胞骨架重排并引起其他宿主细胞的改变，但EPEC引起腹泻的机制尚不清楚。 EPEC触发宿主细胞死亡的发现为EPEC引起疾病的方式提供了重要的影响。 EPEC触发的细胞死亡模式具有凋亡（程序性细胞死亡）和坏死的特征。 EPEC介导的杀戮的非凋亡特征之一是从宿主细胞释放三磷酸腺苷（ATP）。释放后，ATP被分解为其他腺嘌呤核苷酸和腺苷。腺苷本身就是一种有效的秘密捕捉，即肠液和电解质分泌的刺激剂，可能导致或导致腹泻。本应用程序试图了解EPEC如何触发ATP从宿主释放，特别关注囊性纤维化跨膜调节剂（CFTR）的作用。其他目标包括确定激活肠道分泌的腺苷激活的信号传导途径，以及确定腺嘌呤核苷酸释放到感染了Epec类病原体兔腹泻的兔子肠道中的程度