Capturing functional states of type III secretion systems from Chlamydia in situ

许多“友好”的细菌被动地生活在环境中，或者与植物和动物进行有益的交往，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破译这些注射器和效应器是如何工作的。其中一种称为衣原体的致病细菌是造成严重感染的原因。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非常具有挑战性的，因为它们根本不能在宿主细胞外生长。衣原体使用分子注射器来传递效应器，使细菌能够迫使自己进入宿主细胞并在体内复制。我们最近使用电子显微镜对这些传染性细菌进行了非常详细的检查。当细菌的分子注射器第一次接触宿主表面时，我们已经能够看到细菌进入细胞的过程，并更详细地了解细菌是如何进入我们的细胞的。许多科学家通过分离注射器来研究它们，但在这个过程中，重要的部分丢失了。我们提议的实验将检查完整注射器在细菌膜中和接触宿主细胞时的结构。这些发现不仅将提供有关衣原体如何致病的重要新信息，最终可能会导致新的治疗方法，还将提供其他具有非常相似注射器的致病细菌。

Many 'friendly' bacteria live passively in the environment or engage in 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 decipher how these syringes and effectors operate.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 very challenging 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 force their own entry into host cells and to replicate inside. We have recently used electron microscopy to examine these infectious bacteria in great detail. We have been able to see the bacteria in the process of entering cells when their molecular syringe first contacts the host surface and see in much more detail how the bacteria enter into our cells. Many scientists have studied the syringes by isolating them, but in the process important parts are lost. Our proposed experiments will examine the structure of the intact syringe while it is in the bacterial membrane and when it contacts the host cell. The findings will not only provide important new information about how Chlamydia cause disease, which might eventually lead to new treatments, but also other disease-causing bacteria that have very similar syringes.