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Understanding mycobacterial immune stimulation through the study of novel glycoside hydrolases

Primary Supervisor: Dr Patrick Moynihan, School of Biosciences

Secondary supervisor: Dr Andrew Lovering, Birmingham. Elisabeth Lowe, Newcastle

PhD project title: Understanding mycobacterial immune stimulation through the study of novel glycoside hydrolases.

University of Registration: University of Birmingham

Project outline:

Mycobacterial diseases represent one of the single greatest threats to humans. While this is most often considered in the context of human disease, mycobacteria also have a substantial impact on our food supply-chain. One example of this is Mycobacterium avium subsp. paratuberculosis (MAP) which is the causative agent of Johne’s disease in cattle and other ruminants. The presentation of Johne’s disease is similar to the human gastro-intestinal disease Crohn’s, which is hypothesised to also be caused by mycobacteria in some patients. Both of these diseases are driven by a strong inflammatory response in the gut, which in the case of Johne’s is known to be caused by mycobacterial effectors. Despite this knowledge, we have a very limited understanding of the mechanisms employed by these bacteria to release immune stimulating molecules.

Recently, in collaboration with Dr. Elisabeth Lowe in Newcastle we discovered a new structural family of glycoside hydrolases with an unprecedented reaction mechanism. Orthologs of these proteins are found in MAP and some other mycobacteria and are likely to be involved in releasing immunogenic molecules to the host and/or in recycling of these key molecules. In this project the student will explore the biochemical function of these proteins and their role in MAP biology. This will involve the use of biochemistry, structural biology, microbiology and systems-biology approaches. For a similar project lead by Dr. Moynihan see: https://www.nature.com/articles/s41467-019-10586-2.

Through the successful completion of this project the student will gain a firm background in core techniques for a career in the life sciences. The project is structured so that there is an opportunity for the student to follow their curiosity, and the areas of research about which they are most excited. They will be supported at Birmingham by Drs. Moynihan and Lovering. There will also be an opportunity to do research visits to Newcastle, under the supervision of Dr. Elisabeth Lowe who is an expert in glycobiology.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Plant and Crop Science

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 these interesting proteins from two main directions. First, they will work to make single-gene deletions in MAP so that we can probe the role of the protein in the organism. This will involve molecular microbiology and subsequently analytical techniques such as HPLC and thin layer chromatography to understand the impact of losing these genes on mycobacterial biology. The student will also produce and purify these enzymes so that we can study them in vitro, and ultimately determine their structure. This will use classical protein purification and structural biology techniques including X-ray crystallography with the support of Dr. Lovering. Depending on the direction of the project the student may employ some systems biology approaches to look for proteins that work in concert with these new glycoside hydrolases.

Contact: Dr Patrick Moynihan, University of Birmingham