Dissecting the modulation of nucleocytoplasmic signalling, host cell cycle and differentiation by a new family of Legionella protease effectors

嗜肺军团菌和相关细菌是环境微生物，它们可以污染人造水系统，如空调系统或水疗池。人类意外吸入受污染的水可导致严重的肺部感染，称为军团病。感染可能仅限于个人，但如果受污染的水滴随气流分布在广泛的区域，也可能引发数十或数百例的暴发（例如2015年美国纽约和2016年西班牙）。老年人、免疫功能低下的人和有潜在呼吸系统疾病的人最容易感染，但人体中容易感染的确切缺陷，以及细菌用来克服人体免疫防御的武器，目前还没有很好的定义。嗜肺细胞使用一种复杂的运输机制，将大量的蛋白质，即所谓的效应物，注射到人类巨噬细胞中；免疫系统的细胞，专门用来杀死细菌入侵者。这些效应物操纵巨噬细胞的正常功能，使细菌在细胞内持续存在和繁殖，直到资源耗尽，大量细菌被释放，放大感染并对肺部造成损害。了解效应物的功能和发现人类巨噬细胞的弱点是开发新的急需药物来治疗军团菌和其他利用巨噬细胞引起疾病的细菌感染的关键。我们的研究重点是阐明操纵人类细胞的新效应家族的作用。我们发现这些效应物具有切割人类蛋白质、使其失活或改变其功能的强大能力。我们的初步实验表明，其中两种效应物要么针对一个重要的信号中继，它允许人类细胞调整和响应来自其他细胞的信号，要么针对控制细胞分裂和生长的机制。这两个过程都是细胞内稳态和通讯的核心。在这个项目中，我们的目标是揭示这种操作对人类巨噬细胞的功能和防御反应以及细菌引起疾病的潜力的详细机制和后果；有望找到对抗细菌感染的新方法。

Legionella pneumophila and related bacteria are environmental microbes, which can contaminate man-made water systems, such as air conditioning systems or spa-pools. Accidental inhalation of contaminated water by humans can result in a severe lung infection called Legionnaires' disease. Infections can be limited to individual persons, but, if contaminated water droplets are distributed over wide areas with airflow, can also elicit outbreaks with dozens or hundreds of cases (e.g. New York, USA in 2015, and Spain, 2016).The elderly, immunocompromised people and persons with underlying respiratory conditions are at the most risk, but the exact defects in the human body that predispose to infection, and the weapons bacteria employ to overcome human immune defences are not well defined.L. pneumophila uses a sophisticated transport machinery to inject a large number of proteins, so called effectors, into human macrophages; cells of the immune system, which are dedicated to kill bacterial intruders. These effectors manipulate the normal functions of macrophages allowing bacteria to persist and multiply inside the cell until the resources are exhausted and a large number of bacteria are released, amplifying the infection and causing damage to the lung. Understanding the function of effectors and finding the weak points of human macrophages is key to develop new, much needed, drugs to treat infections with Legionella and other bacteria that exploit macrophages to cause disease.Our research focusses on elucidating the role of a new family of effectors that manipulate human cells. We found that these effectors have the powerful ability to cleave human proteins, inactivating them or changing their function. Our preliminary experiments reveal that two of these effectors target either an important signalling relay, which allows human cells to adjust and respond to signals from other cells, or the machinery controlling cell division and growth. Both of these processes are central to cell homeostasis and communication. In this project, we aim to reveal the detailed mechanisms and consequences of this manipulation for the function and defence responses of the human macrophages and for the potential of the bacteria to cause disease; promising to unlock new ways to combat bacterial infections.