PhD project title and outline, including interdisciplinary dimension:
Dissection of protease signalling during bacterial infection for drug and biomarker discovery
Human proteases act at critical decision points of intra- and extracellular signalling processes through irreversible cleavage of key proteins, controlling e.g. cell death, inflammation and tissue remodelling in response to infection. Because of these critical roles and highly destructive potential, proteases are typically tightly regulated and their activation often tailored to a specific microbial threat. Conversely, bacterial pathogens release proteases to destroy or manipulate the host to their benefit. Their key roles in the host-pathogen interplay make proteases promising targets for anti-virulence or immunomodulatory drugs and potential biomarkers of infection.
Legionella species cause Legionnaires’ disease, a potentially fatal pneumonia. They belong to the group of atypical human respiratory pathogens, which often show extra-pulmonary symptoms, are difficult to diagnose and resistant to first line antibiotics. Rapid diagnosis is key for adequate treatment and improved prognosis. L. pneumophila secretes more than 300 proteins, most of which are injected into host cells to subvert and replicate in macrophages and alveolar epithelial cells. The majority does not show homology to known proteins and remains uncharacterised. We recently identified new proteases among them, which seem to target fundamental host processes; however, a systematic characterisation of Legionella proteases or the host protease response during infection has never been undertaken.
This exciting project will use a wide spectrum of techniques, from microbiology, cell and immune biology to biochemistry and chemical biology to profile active proteases and determine their role in Legionella infection and immune response. Close collaboration and placement at ProAxsis, our industrial partner, will not only facilitate the use of state-of-the art protease probes and assessment of the identified proteases as biomarkers or drug targets, but also provide valuable insight in project management and decision making in translational research in a business environment.
Primary supervisor: Dr. Gunnar N. Schroeder (Medicine, Dentistry and Biomedical Science)
Secondary supervisor: Professor Cliff Taggart (Medicine, Dentistry and Biomedical Science)
External Partner/Organisation: ProAxsis