Subversion of actin cytoskeleton dynamics by the WxxxE effector proteins Map, EspM2 and EspS

WxxxE 效应蛋白 Map、EspM2 和 EspS 颠覆肌动蛋白细胞骨架动力学

• 批准号: G0700823/1
• 负责人: Gad Frankel
• 金额: $ 80.57万
• 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: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700823%2F1
• 关键词: Subversion; actin; cytoskeleton; dynamics; WxxxE

Escherichia coli bacteria live in the human gut and are normally harmless. However, several strains of E. coli have acquired additional genes that enable them to inflict damage and cause disease. One example of such pathogenic E. coli, which is among the most important bacterial causes of diarrhoeal disease worldwide and responsible for deaths of hundreds of thousands of babies and young infants in developing countries each year, is enteropathogenic E. coli (EPEC). Like EPEC, other diarrhoeal pathogens, including enterohaemorrhagic E. coli (EHEC), Salmonella and Shigellea are also important enteric pathogens responsible for child morbidity and mortality in developing countries. These pathogens are also common causes of travellers? diarrhoea. Moreover, EHEC infection can lead to haemorrhagic colitis and haemolytic uraemic syndrome (HUS); EHEC-induced HUS is now the leading cause of acute paediatric renal failure in the UK and US. Salmonella typhi is the causative agent of typhoid fever. In both developing and developed countries the economical burden of these diseases is vast. We now know that disease is caused when these bacteria directly inject virulence proteins, known as effectors, into gut cells. Therefore, understanding what these different effectors do inside the cell is crucial to understanding how they cause disease. Based on a common and a critical motif, a number of effector proteins expressed by these pathogens were recently grouped into one category (refer to as the WxxxE effectors). In this study we will focus on three example WxxxE proteins and study their function and role in disease using in vitro (biochemistry and cell culture methodologies) and in vivo models. The study will undoubtedly reveal new insights into the function of WxxxE proteins and mechanisms of bacterial colonisation. Better understanding of these effectors is essential for development of effective treatments and will enhance our general understanding of how pathogenic bacteria hijack cell functions for their own advantage.

大肠杆菌生活在人类肠道中，通常是无害的。然而，几株E.大肠杆菌已经获得了额外的基因，使它们能够造成损害和引起疾病。这种致病性E.大肠杆菌是世界范围内引起腹泻的最重要的细菌之一，每年在发展中国家造成数十万婴儿和幼儿死亡。coli（EPEC）。与EPEC一样，其他肠道病原体，包括肠出血性大肠杆菌。肠出血性大肠杆菌（EHEC）、沙门氏菌和志贺氏菌也是造成发展中国家儿童发病率和死亡率的重要肠道病原体。这些病原体也是旅行者的常见原因吗？腹泻。此外，肠出血性大肠杆菌感染可导致出血性结肠炎和溶血性尿毒综合征（HUS）;肠出血性大肠杆菌诱导的HUS现在是英国和美国急性儿科肾衰竭的主要原因。伤寒沙门氏菌是伤寒的病原体。在发展中国家和发达国家，这些疾病的经济负担是巨大的。我们现在知道，当这些细菌直接将毒力蛋白（称为效应子）注入肠道细胞时，就会引起疾病。因此，了解这些不同的效应物在细胞内的作用对于了解它们如何引起疾病至关重要。基于一个共同的和关键的基序，这些病原体表达的一些效应蛋白最近被分为一类（称为WxxxE效应）。在这项研究中，我们将集中在三个例子WxxxE蛋白和研究它们的功能和疾病中的作用，使用体外（生物化学和细胞培养方法）和体内模型。这项研究无疑将揭示WxxxE蛋白的功能和细菌定植机制的新见解。更好地了解这些效应子对于开发有效的治疗方法至关重要，并将增强我们对病原菌如何劫持细胞功能以获得自身优势的总体理解。