Recognition by the type II secretion system and how it enables Legionella pneumophila to thrive

II 型分泌系统的识别及其如何使嗜肺军团菌茁壮成长

• 批准号: MR/M009920/1
• 负责人: James Garnett
• 金额: $ 46.56万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM009920%2F1
• 关键词: Recognition; type; II; secretion; system

Bacteria are tiny organisms that are present in a wide range of environments on the earth. They can also live within humans and animals where they have both positive and negative benefits to health. In this application I propose a number of experiments to understand certain aspects of how some bacteria cause disease and persist in the environment. Specifically I will be studying Legionella pneumophila, a bacterium that is readily found in both natural and man-made water environments. This bacterium infects the human lungs and causes Legionnaires' disease, an often-fatal type of pneumonia, and Pontiac fever, a milder flu-like disease. Man-made infrastructures that store and distribute water are ubiquitous in Western society and as such Legionella are found in many large buildings (including hospitals and hotels), with the number of Legionnaires' disease cases on the increase. The high prevalence of L. pneumophila within the environment is due to its ability to survive inside biofilms: complex multispecies bacterial masses encased in a defensive layer. Here the inhabitants are protected from the environment, other organisms and antibacterial compounds. However, water-borne amoebae can still graze on these bacteria, although L. pneumophila has developed strategies to survive by going inside them, evading their detection and hiding away from any attack. Unfortunately, some types of mammalian lung cells share similarities with various amoeba strains and this is why Legionella is an opportunistic pathogen that can cause disease when humans come into contact with contaminated water.Legionella use a 'type II secretion system' (T2SS), a syringe-like mechanism to transport protein substrates into their surroundings. These substrates promote the formation of biofilms and enable L. pneumophila to become fully virulent. They have also been shown to contribute to this bacterium's extensive host range. For example, at least 18 strains of amoeba are the natural hosts of L. pneumophila creating a substantial environmental reservoir of this pathogen. For some of these substrates, however, we do not understand exactly what they target or what their specific roles are, although several have been linked to disease and the ability of L. pneumophila to infect a broad range of amoebae. Analysing which of these proteins are important for these processes will be one aspect of what I shall be investigating but my main objective is to study how L. pneumophila recognizes these substrates before they are secreted. Understanding the details of how this T2SS deploys these substrates will provide the foundations to design compounds that can disarm it. Furthermore, this type of secretion system is also essential for many other human bacterial pathogens, to discharge toxins for example, into the host and cause disease. Therefore in turn, these studies may also reveal a common novel pathway to combat other types of bacterial infections in the future.

细菌是存在于地球上各种环境中的微小生物体。它们还可以生活在人类和动物体内，对健康既有积极的影响，也有消极的影响。在此应用中，我提出了一些实验来了解某些细菌如何引起疾病并在环境中持续存在的某些方面。具体来说，我将研究嗜肺军团菌，这是一种在天然和人造水环境中很容易发现的细菌。这种细菌感染人类肺部并引起军团病（一种通常致命的肺炎）和庞蒂亚克热（一种较温和的流感样疾病）。储存和分配水的人造基础设施在西方社会无处不在，因此在许多大型建筑物（包括医院和酒店）中都发现了军团菌，军团病病例数量不断增加。嗜肺军团菌在环境中的高患病率是由于其能够在生物膜内生存的能力：生物膜是包裹在防御层中的复杂的多物种细菌团。在这里，居民免受环境、其他生物和抗菌化合物的影响。然而，水生变形虫仍然可以吃这些细菌，尽管嗜肺军团菌已经发展出通过进入这些细菌内部、逃避它们的检测并躲避任何攻击来生存的策略。不幸的是，某些类型的哺乳动物肺细胞与各种变形虫菌株有相似之处，这就是为什么军团菌是一种机会性病原体，当人类接触受污染的水时，可能​​会导致疾病。军团菌使用“II 型分泌系统”(T2SS)，这是一种类似注射器的机制，将蛋白质底物运输到周围环境中。这些底物促进生物膜的形成，并使嗜肺军团菌变得完全有毒。它们还被证明有助于这种细菌的广泛宿主范围。例如，至少 18 种阿米巴原虫菌株是嗜肺军团菌的天然宿主，形成了该病原体的大量环境储存库。然而，对于其中一些底物，我们并不确切地了解它们的目标是什么或它们的具体作用是什么，尽管其中一些底物与疾病和嗜肺军团菌感染广泛的阿米巴原虫的能力有关。分析哪些蛋白质对这些过程很重要将是我要研究的一个方面，但我的主要目标是研究嗜肺军团菌如何在分泌这些底物之前识别它们。了解 T2SS 如何部署这些基质的细节将为设计可解除其武装的化合物奠定基础。此外，这种类型的分泌系统对于许多其他人类细菌病原体也至关重要，例如将毒素释放到宿主体内并引起疾病。因此，反过来，这些研究也可能揭示未来对抗其他类型细菌感染的共同新途径。

项目成果

Scalable Geometrically Designed Protein Cages Assembled via Genetically Encoded Split Inteins

通过基因编码的分裂内含肽组装可扩展的几何设计蛋白质笼

• DOI: 10.2139/ssrn.3288532
• 发表时间: 2018
• 期刊: SSRN Electronic Journal
• 作者: Wright J

Type II Secretion-Dependent Aminopeptidase LapA and Acyltransferase PlaC Are Redundant for Nutrient Acquisition during Legionella pneumophila Intracellular Infection of Amoebas.

• DOI: 10.1128/mbio.00528-18
• 发表时间: 2018-04-17
• 期刊: mBio
• 影响因子: 6.4
• 作者: White RC;Gunderson FF;Tyson JY;Richardson KH;Portlock TJ;Garnett JA;Cianciotto NP
• 通讯作者: Cianciotto NP

Scalable Geometrically Designed Protein Cages Assembled via Genetically Encoded Split Inteins.

通过基因编码的分裂内含肽组装的可扩展几何设计的蛋白质笼。

• DOI: 10.1016/j.str.2019.02.005
• 发表时间: 2019
• 期刊: 1993)
• 作者: Wright JN

Structure and functional analysis of the Legionella pneumophila chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation.

嗜肺军团菌几丁质酶 ChiA 的结构和功能分析揭示了金属依赖性粘蛋白降解的新机制。

• DOI: 10.1371/journal.ppat.1008342
• 发表时间: 2020
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Rehman S

Assay for Assessing Mucin Binding to Bacteria and Bacterial Proteins.

评估粘蛋白与细菌和细菌蛋白结合的测定。

• DOI: 10.21769/bioprotoc.3933
• 发表时间: 2021
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Grigoryeva LS