Understanding and exploiting regulation in pathogenic enteroaggregative Escherichia coli

许多细菌引起人类腹泻，因为当它们被摄入时，它们通过附着在肠道内壁而在下消化道定植。然后，它们产生的产物会导致宿主肠道中液体积聚的异常水平。对大多数人来说，这种腹泻只是一种刺激，但对一些人来说，它可能危及生命。目前，在发达国家和发展中国家，引起腹泻的一个特别棘手的原因是肠聚集性大肠杆菌（EAEC）。这种有害的微生物可能是从无害的大肠杆菌菌株进化而来的，在获得了几十个额外的基因后，这些基因使它能够附着在人类肠道上并引起腹泻。对EAEC和其他有害细菌的研究表明，这些导致疾病的额外基因的表达受到严格控制。对于EAEC和相关的有害细菌，我们现在知道主要的调节剂是什么。有趣的是，这些调节因子中最重要的是与其他额外基因一起获得的，它的作用似乎主要是确保有害细菌只在宿主中表达致病基因。因此，这里提出的工作的主要目的是做实验，告诉我们当细菌到达肠道时，主要调节器是如何激活的，以及调节器的活性是如何打开和关闭的。我们计划研究来自不同国家患者的EAEC菌株，以确定是否总是使用相同的机制，并检查不同菌株中的有害基因。一旦我们了解了调节器是如何工作的，我们将使用基因工程技术来制造有缺陷的调节器衍生物，从而干扰有毒菌株。我们将设计出在感染过程中将有缺陷的调节剂输送到有害细胞的方法，以期开发出一种治疗细菌感染的新方法，这种方法涉及“解除”有害细菌而不是杀死它们。

Many bacteria cause diarrhoea in humans because, when they are ingested, they colonise the lower gut by attaching to the lining of the intestine. They then produce products that cause abnormal levels of fluid build-up in the host's gut. For most people, such diarrhoea is merely an irritation, but, for some, it can be life-threatening. Currently, one especially troublesome cause of diarrhoea, in both developed and developing countries, is enteroaggregative Escherichia coli (EAEC). This harmful organism probably evolved from harmless Escherichia coli strains following the acquisition of a score or so of extra genes that allow it to attach to human intestines and cause diarrhoea. Studies with EAEC and with other harmful bacteria have shown that the expression of these extra genes, which cause disease, is tightly controlled. For EAEC, and related harmful bacteria, we now know what the principal regulators are. Interestingly, the most important of these regulators was acquired with the other extra genes, and its role appears to be mainly to make sure that the harmful bacteria only express the disease-causing genes when the harmful bacteria are in the host. Hence the main aims of the work proposed here are to do experiments that will tell us how the main regulator is activated when the bacteria get to the gut, and how the activity of the regulator is turned on and turned off. We plan to look at EAEC strains from patients from different countries to see if the same mechanism is always used and also to check the harmful genes in the different strains. Once we have understood how the regulator works, we will use genetic engineering techniques to make derivatives of the regulator that are defective and so will interfere with virulent strains. We will devise ways to deliver the defective regulator to harmful cells during infection with a view to developing a new way to treat bactreial infection that involves 'disarming' the harmful bacteria rather than killing them.