Defining early events underpinning Chlamydia trachomatis entry into mammalian host cells

许多“友好”细菌被动地生活在环境中，或与植物和动物建立互惠互利的关系，例如通过固定营养或帮助消化。其他细菌已经获得了在更复杂的有机体中生活的能力，它们在那里生存和繁殖。尽管这些侵略性细菌能够为了自己的利益而扩张这些‘宿主’微生物，但它们也会对宿主造成损害，从而导致疾病。医生已经用抗生素治疗了人和动物的这种细菌感染，但最近细菌对这些药物的抗药性越来越强。因此，在分子水平上了解不同的细菌是如何导致疾病的至关重要，因为这将为治疗患者和开发保护性疫苗的新方法提供线索。研究表明，这些细菌中的许多都部署了一种复杂的武器，其作用类似于微小的注射器，向宿主细胞注入一种名为“效应器”的细菌蛋白质混合物。目前生物医学研究的一个重要焦点是检测这些注射器和效应器是如何工作的。值得注意的是，到目前为止的结果不仅开始告诉我们有多少细菌导致疾病，而且它们还为我们自己的细胞如何运作提供了惊人的新见解，因为细菌数百万年来一直在完善自己的武器。矛盾的是，这些细菌效应器因此也为研究细胞生物学提供了精致而令人兴奋的新工具。其中一种致病细菌被称为衣原体，它是严重感染的罪魁祸首。它是英国和其他发达国家性传播疾病和不孕不育的主要细菌原因，也是一种被世界卫生组织指定为被忽视的热带疾病的普遍失明形式沙眼的主要原因。在实验室研究衣原体是很困难的，因为它们根本不能在宿主细胞外生长。衣原体使用一个分子注射器来传递效应器，使细菌能够进入宿主细胞，并在一个特殊的膜结合的隔间内进行复制，这种隔间被称为“包涵体”。我们最近描述了更多关于细菌如何进入宿主细胞的情况。衣原体通过干扰被称为肌动蛋白细胞骨架的丝状网络来实现这一点，该网络的作用类似于细胞支架。这种支架控制细胞的形状、内部结构的位置以及它们如何分裂。我们拟议的实验将详细研究衣原体效应器如何重新排列这种支架，以允许细菌成功进入人类细胞。这些发现不仅将提供关于衣原体如何导致疾病的重要新信息，最终可能导致新的治疗方法，还可能阐明细胞用来控制其结构的基本途径。

Many 'friendly' bacteria live passively in the environment or engage in mutually beneficial associations with plants and animals, for example by fixing nutrients or assisting digestion. Other bacteria have gained the ability to live inside more complex organisms where they survive and multiply. Although able to expend these 'host' organisms for their own advantage, these aggressive bacteria also cause damage to the host, which results in disease. Doctors have treated such bacterial infections in man and animals with antibiotics, yet recently bacteria are increasingly developing resistance to these drugs. Consequently, it is crucial to understand how different bacteria cause disease at a molecular level, as this will provide clues to new ways to treat patients and develop protective vaccines. It has emerged that many of these bacteria deploy a sophisticated weapon that acts like a minute syringe to inject host cells with a cocktail of bacterial proteins called 'effectors'. An important focus of current biomedical research is to detect how these syringes and effectors operate. Remarkably, the results so far are not only beginning to tell us how many bacteria cause disease, but they are also providing astonishing new insights into how our own cells function, as the bacteria have been perfecting their armaments for millions of years. Paradoxically, these bacterial effectors therefore also provide exquisite and exciting new tools to study cell biology.One of these disease-causing bacteria called Chlamydia is responsible for serious infections. It is the main bacterial cause of sexually transmitted disease and infertility in the U.K. and other developed countries, and of a widespread form of blindness called 'trachoma', which is designated as a neglected tropical disease by the World Health Organisation. It is difficult to study Chlamydia in the laboratory as they cannot grow outside host cells at all. Chlamydia use a molecular syringe to deliver effectors that enable the bacteria to enter into host cells and replicate inside a special membrane-bound compartment inside called the 'inclusion'. We have recently described more about how the bacteria enter their host cells. Chlamydia achieve this by interfering with a filament-like network called the actin cytoskeleton that acts like cellular scaffolding. This scaffolding controls the shape of cells, the position of their internal structures and how they divide. Our proposed experiments will examine in detail how chlamydial effectors rearrange this scaffolding to allow the bacteria to successfully enter inside human cells. The findings will not only provide important new information about how Chlamydia cause disease, which might eventually lead to new treatments, it might also illuminate the fundamental pathways cells employ to control their architecture.