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

原位捕获衣原体 III 型分泌系统的功能状态

• 批准号: MR/N000846/2
• 负责人: Richard Hayward
• 金额: $ 29.85万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN000846%2F2
• 关键词: Capturing; functional; states; type; III

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.

许多“友好”的细菌被动地生活在环境中，或者与植物和动物建立有益的联系，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生物体内生存和繁殖的能力。虽然能够消耗这些“宿主”生物体为自己的利益，这些侵略性的细菌也造成损害的主机，从而导致疾病。医生已经用抗生素治疗了人类和动物的这种细菌感染，但最近细菌对这些药物的耐药性越来越强。因此，了解不同细菌如何在分子水平上引起疾病至关重要，因为这将为治疗患者和开发疫苗的新方法提供线索。已经发现，这些细菌中的许多都部署了一种复杂的武器，就像一个微型注射器一样，向宿主细胞注射一种称为“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解这些注射器和效应器是如何工作的。其中一种叫做衣原体的致病细菌是造成严重感染的原因。它是英国性传播疾病和不孕不育的主要细菌原因。及其他已发展国家，以及一种名为“沙眼”的广泛失明形式，被世界卫生组织指定为一种被忽视的热带疾病。在实验室中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传递效应物，使细菌能够迫使自己进入宿主细胞并在内部复制。我们最近使用电子显微镜对这些传染性细菌进行了详细的检查。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，并更详细地看到细菌如何进入我们的细胞。许多科学家通过分离来研究注射器，但在这个过程中，重要的部分丢失了。我们提出的实验将检查完整的注射器的结构，而它是在细菌膜和当它接触宿主细胞。这些发现不仅将提供有关衣原体如何引起疾病的重要新信息，这可能最终导致新的治疗方法，而且还将提供其他具有非常相似注射器的致病细菌。

项目成果

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry.

• DOI: 10.1371/journal.ppat.1007051
• 发表时间: 2018-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Ford C;Nans A;Boucrot E;Hayward RD
• 通讯作者: Hayward RD