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

大肠杆菌构成正常肠道植物群的一部分，而几种菌株获得了额外的基因，使它们能够引起疾病。肠致病性大肠杆菌（EPEC）和肠出血性大肠杆菌（EHEC，已知的E.大肠杆菌O 157）在向哺乳动物细胞中注入称为效应子的特定毒力蛋白时引起疾病。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E.大肠杆菌O 157：H7），在发达国家占主导地位，引起腹泻、出血性结肠炎和溶血性尿毒综合征;年轻人和老年人面临的风险最大。据估计，CA。在美国和英国，每年分别有73，000和1，000人感染肠出血性大肠杆菌。在英国和美国，肠出血性大肠杆菌引起的溶血性尿毒综合征是导致儿童急性肾功能衰竭的主要原因。阐明EPEC和EHEC的感染策略完全依赖于识别效应物靶向的蛋白质和信号转导途径。本项目的目的是研究几个关键的EPEC和EHEC效应子在感染过程中的生理作用。我们将首先研究EPEC和EHEC效应子Tir和EspT在培养的人类细胞中破坏信号传导的机制。然后，我们将使用EPEC和EHEC小鼠模型确定将实验室收集的数据转化为肠道感染。在体内研究致病机理对于理解宿主病原体相互作用是必不可少的。在进行动物实验时，我们特别注意3R原则。事实上，我们的感染模型赢得了2006年NC 3Rs奖。补液和营养补充是唯一有效的治疗EPEC和肠出血性大肠杆菌感染;抗生素治疗是反生产。HUS患者可能需要透析，严重者需要肾移植。目前没有针对EPEC和EHEC感染的疫苗或特异性治疗。更好地了解定殖过程和毒力因子的作用对于开发新的特异性和有效的治疗方法至关重要。

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.