Functional genomics approaches to manipulating Bordetella pertussis outer membrane synthesis for vaccine development

Supervisory team:
Dr Andrew Preston, University of Bath (lead supervisor)
Dr Rosanna Leuzzi, GSK Biologicals, Siena (industrial co-supervisor)

The outer membrane (OM) is a critical component of the Gram negative bacterial cell. It is a crucial structural component, a vital permeability barrier, has many critical interactions with other components of the cell wall and represents the key interface between the bacterium and its environment. The OM is of great interest for understanding bacterial physiology and has direct implications in the field of vaccinology. Many key antigens of bacterial pathogens are OM located molecules, both protein and non-protein, and the use of OM vesicles as antigen delivery systems has been widely investigated.

Biogenesis of the OM involves synthesis of membrane components, including lipids, sugars and proteins, their export across the inner membrane and periplasm and the correct assembly at the cell surface. Cell growth requires this be a continuous process while OM composition can vary in response to both internal and external stimuli. Thus, OM synthesis and maintenance is a highly regulated and complex process.

Bordetella pertussis is the causative agent of whooping cough, or pertussis, that is resurgent in a number of countries despite high vaccination coverage. Current acellular pertussis vaccines induce suboptimal protection and there is great interest in the development of novel vaccines, particularly vaccines containing a more complex repertoire of antigens than current acellular vaccines, and those containing both protein and non-protein antigens. OM based vaccines would provide this mix of antigens. However, little is known about mechanisms that maintain B. pertussis OM integrity or regulate the OM, including that of vesicle formation. Preliminary data reveal cell wall biosynthesis can vary in B. pertussis, dependent of the activity of a transcriptional regulator, suggesting that it can be genetically manipulated.

This project will combine cutting edge functional genomics approaches with molecular microbiology to dissect mechanisms involved in maintenance of OM stability, synthesis and assembly in this important bacterial pathogen. In turn this will identify the appropriate tools to manipulate B. pertussis OM for the purposes of generating modified OM fractions, or OM vesicles. The project is a collaboration between the University of Bath and GSK Vaccines in Siena. The student will be based in Bath but receive significant input from GSK scientists and conduct some studies at the Siena site. The project will provide training in functional genomics, bioinformatics, and molecular microbiology. The student will greatly benefit from interactions with the industry partner and through this experience diverse training environments.

Applicants should hold, or expect to receive, a First Class or high Upper Second Class UK Honours degree (or the equivalent qualification gained outside the UK) in a relevant subject. A master’s level qualification would also be advantageous.

Informal enquiries are welcomed and should be directed to Dr Andrew Preston, [Email Address Removed].

Formal applications should be made via the University of Bath’s online application form:
https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-FP02&code2=0013

Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section.

More information about applying for a PhD at Bath may be found here:
http://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/

Anticipated start date: as soon as possible (and by the end of August at the latest).