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A systems biology approach to understanding mycobacterial diversity

Primary Supervisor: Dr Patrick Moynihan, School of Biosciences

Secondary supervisor: Manuel Banzhaf

PhD project title: A systems biology approach to understanding mycobacterial diversity

University of Registration: University of Birmingham

Project outline:

Amongst bacteria mycobacteria are distinguished by having one of the most complex and interesting cell walls. This structure is a significant contributor to the virulence of many pathogens of both agriculturally important animals such as cows (e.g. Mycobacterium bovis) and humans (e.g. Mycobacterium tuberculosis). While global efforts have been made to understand the biosynthesis, remodeling and degradation of this exquisite structure, much remains unknown. Critically, we do not understand how mycobacteria program variability into their cell surface, so that they can modulate the host during infection. My group has recently discovered a group of novel enzymes that modify the mycobacterial cell surface, raising the question of how these enzymes are controlled and regulated.

In this project the student will leverage our single-gene deletion library in Mycobacterium bovis BCG to develop a genome wide response map for cell surface variability. This will be achieved using specialised reporter cell lines and high-throughput robotics. Furthermore, the student will use cutting edge genetic tools including CRISPR to generate targeted deletions in pathogenic mycobacteria including animal and human pathogens. They will also gain experience in protein biochemistry and structural biology as they characterise selected proteins identified in their screens.

In general, there is a lot of scope for the student to pursue aspects of the project they find most interesting, and they will be supported in this at all stages. This project is designed to give the student a broad skillset to help prepare them for a career in biosciences. 

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Animal Health and Welfare & Understanding the Rules of Life: Microbiology  

    Techniques that will be undertaken during the project:

    My laboratory employs a wide range of techniques to answer fundamental questions about bacterial biology (see: https://www.nature.com/articles/s41467-019-10586-2). In this project the student will tackle their research question from two main directions. First, they will gain experience cultivating mycobacteria and infecting reporter cell lines. This will involve working with high-throughput robotics and cutting-edge technologies to determine a genome-wide response map in collaboration with Dr. Banzhaf. The student will take these data and depending on their interest can investigate the function of identified genes in a several ways. First, through protein biochemistry by recombinantly producing and purifying target proteins and structural biology techniques including X-ray crystallography. The student can also investigate function through bacterial cell biology using knock-out strains of the bacteria, available fluorescent probes and a range of analytical techniques including mass spectrometry.

    Contact: Dr Patrick Moynihan, University of Birmingham