Deciphering the role of the host endoplasmic reticulum in Chlamydia inclusion biogenesis

许多“友好”细菌被动地生活在环境中，或与植物和动物进行互利的联系，例如通过固定营养物质或协助消化。其他细菌已经获得了在更复杂的生物体中生存和繁殖的能力。虽然这些具有侵略性的细菌能够为自己的利益而消耗这些“宿主”生物，但它们也会对宿主造成损害，从而导致疾病。医生们用抗生素治疗人类和动物的这种细菌感染，但最近细菌越来越多地对这些药物产生耐药性。因此，了解不同细菌如何在分子水平上引起疾病是至关重要的，因为这将为治疗患者和开发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，就像一个微小的注射器，向宿主细胞注入一种名为“效应器”的细菌蛋白质混合物。当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的工作原理。值得注意的是，到目前为止，这些结果不仅开始告诉我们有多少细菌引起疾病，而且还为我们自己的细胞如何运作提供了令人惊讶的新见解，因为细菌在数百万年的时间里一直在完善它们的武器。矛盾的是，这些细菌效应物因此也为研究细胞生物学提供了精致和令人兴奋的新工具。其中一种叫做衣原体的致病细菌会导致严重的感染。在英国和其他发达国家，它是导致性传播疾病和不孕症的主要细菌，也是一种被称为“沙眼”的广泛失明的细菌，沙眼被世界卫生组织指定为被忽视的热带疾病。在实验室里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，而且与其他细菌不同，它们还不能进行基因操纵。衣原体使用分子注射器递送效应器，使细菌能够在宿主细胞内称为“内含物”的特殊膜结合隔室内复制。我们最近表明，包涵体与一个重要的宿主膜系统相互作用，称为内质网（ER），它制造宿主蛋白质。我们发现这种新的相互作用对细菌的生存和传染性至关重要。事实上，内质网在细菌组装注射器的地方与包涵体接触，这种结构我们称之为“病原体突触”。我们提出的实验将研究为什么这种与ER的相互作用如此重要，以及它如何与通过注射器输送效应器有关。这些发现不仅将提供衣原体如何致病的重要新信息，这可能最终导致新的治疗方法，还可能阐明细胞用来控制细胞内区室和自身蛋白质合成的基本途径。

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 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 and unlike other bacteria they cannot yet be genetically manipulated. Chlamydia use a molecular syringe to deliver effectors that enable the bacteria to replicate inside a special membrane-bound compartment inside host cells called the 'inclusion'. We have recently shown that the inclusion interacts with an important host membrane system called the endoplasmic reticulum (ER), which manufactures host proteins. We showed that this novel interaction is critical to bacterial survival and infectivity. In fact, the ER contacts the inclusion at the points where the bacteria assemble their syringes, structures we call 'pathogen synapses'. Our proposed experiments will examine why this interaction with the ER is so important and how it might relate to the delivery of effectors through the syringe. 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 use to control their intracellular compartments and the synthesis of their own proteins.