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

大肠杆菌构成了正常肠道菌群的一部分，而几个菌株获得了使它们能够致病的额外基因。肠道致病性(EPEC)和肠出血性大肠杆菌(EHEC，已知的E.ColiO157)在将特定的毒力蛋白(称为效应器)注入哺乳动物细胞时会导致疾病。EPEC是发展中国家婴儿腹泻、发病率和死亡率的主要原因。肠出血性大肠杆菌(尤其是O157：H7大肠杆菌)在发达国家占主导地位，可引起腹泻、出血性结肠炎和溶血性尿毒症综合征；年轻人和老年人风险最大。据估计，美国和英国每年分别约有7.3万人和1000人感染EHEC。EHEC引起的HUS是英美两国儿科急性肾功能衰竭的主要原因。确定EHEC和EHEC的感染策略完全依赖于对效应器靶向的蛋白质和信号转导途径的识别。本项目的目的是研究EPEC和EHEC的几个关键效应分子在感染过程中的生理作用。我们首先将研究EPEC和EHEC效应分子TIR和EspT在培养的人细胞内颠覆信号的机制。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换为肠道感染。体内致病机制的研究是了解宿主病原体相互作用的基础。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NC3Rs奖。补液和营养补充是EPEC和EHEC感染的唯一有效治疗方法；使用抗生素治疗则适得其反。HUS患者可能需要透析，在严重情况下还需要肾移植。目前还没有针对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子的作用对于开发新的特效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.