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This project is now closed

Systems biology of amino acid biosynthesis in Mycobacterium tuberculosis lineages

Project supervisor: Douglas Young (Mycobacterial Research)

Mycobacterium tuberculosis has co-evolved with modern humans over 70 thousand years, diversifying into seven phylogenetic lineages with differing epidemiological profiles. We are interesting in exploring the impact of genetic diversity of the pathogen on its functional biology; particularly in genetic changes that influence the way that bacteria interact with their human hosts during infection and their response to drug treatment. The specific objective of the proposed project is to analyse diversity of M. tuberculosis clinical isolates at the level of amino acid metabolism.

The project will involve integration of bioinformatic and experimental components. Whole genome sequences from a panel of over 300 clinical isolates representative of the seven lineages of M. tuberculosis will be screened for single nucleotide polymorphisms affecting genes that are predicted to be involved in amino acid synthesis and degradation pathways. Selected strains will be tested experimentally to identify phenotypic consequences of genetic diversity by RNA sequencing and by targeted mass spectrometry-based metabolomic profiling using stable isotopic labels. Genotype-phenotype correlations will be confirmed by gene replacement studies, followed by survival assays to investigate potential fitness costs in infection models

Altogether, this systems-level study will inform for the first time on the robustness of amino acid biosynthesis networks across multiple lineages of M. tuberculosis and the relationship between amino acid biosynthesis and host-pathogen interactions. In addition, these studies may identify fragile metabolic points which can be targeted for future drug discovery. The student will gain practical experience in high-throughput ‘omics technologies and their integration into a computational framework, in the context of a major human disease.

References

Portevin, D; Gagneux, S; Comas, I and Young, D (2011)
Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.
PLoS Pathogens 7, e1001307 PubMed abstract
Arnvig, KB; Comas, I; Thomson, NR; Houghton, J; Boshoff, HI; Croucher, NJ; Rose, G; Perkins, TT; Parkhill, J; Dougan, G and Young, DB (2011)
Sequence-based analysis uncovers an abundance of non-coding RNA in the total transcriptome of Mycobacterium tuberculosis.
PLoS Pathogens 7, e1002342 PubMed abstract
de Carvalho, LPS; Fischer, SM; Marrero, J; Nathan, C; Ehrt, S and Rhee, KY (2010)
Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates.
Chemistry & Biology 17, 1122-1131 PubMed abstract