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

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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.