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Bovine and human tuberculosis: probing the genetic, molecular and structural basis of lipid-mediated pathogenesis mechanisms

Principal Supervisor: Dr. Apoorva Bhatt - School of Biosciences

Co-supervisor: Prof. Robin May

PhD project title: Bovine and human tuberculosis: probing the genetic, molecular and structural basis of lipid-mediated pathogenesis mechanisms

University of Registration: University of Birmingham

Project outline:

Sequenced genomes of mycobacteria, including the bovine TB pathogen Mycobacterium bovis and it’s ‘cousin’ the human pathogen Mycobacterium tuberculosis, reveal a number of genes dedicated to lipid biosynthesis and transport. These unique lipids confer a distinct quality to the mycobacterial cell wall, and play an important role in biofilm formation, adhesion, immunomodulation , virulence. Research in the lab in the past has focussed on deciphering the genetic pathways that define lipid biosynthesis and transport in pathogenic mycobacteria. With the use of defined mutant strains defective in the production of relevant lipid species, we plan to test the molecular mechanisms underlying the processes of lipid mediated:

  1. Adhesion and invasion.
  2. Survival inside infected macrophages.
  3. Modulation of the immune system.
  4. Biofilm formation.
  5. Differing host specificity (human vs bovine).

Additionally, we would also like to exploit lipid biosynthesis-related mycobacterial enzymes and transporters as potential drug targets, by gaining insights into their structure for drug interaction studies.

References: 

  1. Varela C., Rittmann D., Singh A., Krumbach K., Bhatt K., Eggeling L., Besra G.S. and Bhatt A. (2012) MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol 19:498-506.
  2. Bhatt A., Brown A.K., Singh A., Minnkin D.E. and Besra G.S. (2008) Loss of a mycobacterial gene encoding a reductase leads to an altered cell wall containing -oxo-mycolic acid analogs and accumulation of ketones. Chem Biol 15: 930-939.

BBSRC Strategic Research Priority: Food Security

Techniques that will be undertaken during the project:

  • Protein expression and purification
  • Biophysical characterisation of proteins
  • Infection of mammalian cells with pathogenic mycobacteria
  • Lipid analysis methodology including TLC, Mass Spectroscopy and NMR
  • Generation of gene knockouts and recombinant strains of pathogenic mycobacteria
  • RNA Seq of bacterial transcripts

Contact: Dr Apoorva Bhatt, University of Birmingham