Subversion of actin signaling pathways by enterohaemorrhagic and enteropathogenic E. coli

肠出血性和肠病性大肠杆菌对肌动蛋白信号通路的破坏

• 批准号: G0901350/1
• 负责人: Gad Frankel
• 金额: $ 15.84万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901350%2F1
• 关键词: Subversion; actin; signaling; pathways; enterohaemorrhagic

Escherichia coli constitute part of the normal gut flora, while several strains acquired additional genes that enable them to cause disease. Enteropathogenic (EPEC) and enterohaemorrhagic Escherichai coli (EHEC, known E. coli O157) cause disease when they inject specific virulence proteins, known as effectors, into the mammalian cell. EPEC is the leading cause of infantile diarrhoea, morbidity and mortality in developing countries. EHEC (particularly E. coli O157:H7), which is predominant in developed countries, cause diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome (HUS); the young and the elderly are most at risk. It is estimated that ca. 73,000 and 1,000 human EHEC infections occur in the US and the UK each year, respectively. EHEC-induced HUS is the leading cause of acute paediatric renal failure in the UK and US.Elucidating the infection strategy of EPEC and EHEC is totally dependent on the identification of proteins and signal transduction pathways that are targeted by the effectors. The aim of this project is to investigate the physiological role of several key EPEC and EHEC effectors during infection.We will first investigate the mechanism by which the EPEC and EHEC effectors Tir and EspT subvert signalling within human cells in culture. We will then determine translate the data gathered in the laboratory to gut infection using an EPEC and EHEC mouse model. Studying pathogenesis in vivo is essential for understanding host pathogen interaction. While conducting animal experiments we take particular care of the 3Rs principals. Indeed, our infection model won the 2006 NC3Rs prizes. Rehydration and nutritional supplementation are the only effective treatments for EPEC and EHEC infection; treatment with antibiotics is countered productive. HUS patients may require dialysis and in sever cases kidney transplantation. No vaccines or specific treatment are currently available against EPEC and EHEC infections. Better understanding of colonisation processes and the role of virulence factors is essential for the development of new specific and effective treatments.

大肠杆菌构成了正常肠道菌群的一部分，而几种菌株获得了使它们引起疾病的其他基因。当将特定的毒力蛋白（称为效应子）注入哺乳动物细胞时，肠病毒（EPEC）和肠胃病（EHEC，已知的大肠杆菌O157）会引起疾病。 EPEC是发展中国家婴儿腹泻，发病率和死亡率的主要原因。 EHEC（尤其是大肠杆菌O157：H7），在发达国家中占主导地位，引起腹泻，出血性结肠炎和汗血症尿毒症综合征（HUS）；年轻人和老年人最有风险。据估计CA。每年分别在美国和英国发生73,000和1,000人EHEC感染。 EHEC诱导的HUS是英国和美国急性小儿肾衰竭的主要原因。确定EPEC和EHEC的感染策略完全取决于效应子靶向的蛋白质和信号转导途径的鉴定。该项目的目的是研究感染过程中几种关键EPEC和EHEC效应子的生理作用。我们将首先研究EPEC和EHEC效应子TIR和ESPT un培养物中人类细胞内信号传导的机制。然后，我们将使用EPEC和EHEC小鼠模型来确定将在实验室中收集的数据转化为肠道感染。在体内研究发病机理对于理解宿主病原体相互作用至关重要。在进行动物实验时，我们特别照顾3RS校长。确实，我们的感染模型赢得了2006年NC3RS奖品。补液和营养补充是EPEC和EHEC感染的唯一有效治疗方法。用抗生素治疗的生产力是应对的。 HUS患者可能需要透析，在隔离为肾脏移植的情况下。目前尚无针对EPEC和EHEC感染的疫苗或特定治疗方法。更好地了解定植过程和毒力因素的作用对于开发新的特定和有效治疗是必不可少的。