Applying -omics technology to understand host-pathogen interactions during Mycobacterium tuberculosis infection

The purpose of this PhD is to investigate host-pathogen interactions during Mycobacterium tuberculosis (Mtb) infection; the bacterium which causes tuberculosis (TB). I aim to further explore and understand why some individuals infected with Mtb remain latently infected (i.e. show no symptoms of the disease) for long periods of time and others get active TB (i.e. show symptoms). We will analyse changes in gene expression (RNA), metabolites, and other markers of both the host and the pathogen during infection and treatment. Understanding such interactions will aid in the development of new vaccines, diagnostic tools and therapeutic interventions which are urgently needed to control TB.

To achieve these aims we will use both a well-established in vitro mycobacterial infection assay to undertake cutting-edge -omics profiling technologies, specifically dual RNA-sequencing (RNA-seq) and liquid-chromatography mass spectrometry (LC-MS). Dual RNA-seq is a novel method of sequencing both the host and pathogen gene expression through measuring RNA in a single experiment. In tandem, LC-MS will be carried out to determine changes in metabolite and lipid levels. Metabolite and lipid analysis provide a direct read-out of the activities of a cell. This approach will allow the dialogue between host and pathogen to be monitored throughout the infection. Sample collection, infection strategies and sample preparation methodologies will be established.

Bioinformatics analysis will be carried out to correlate the dual RNA-seq and LC-MS experiments in order to discover how the host and bacteria influence each other during infection and how this can lead to the progression of the infection or protection against the disease. Finally, the most interesting and/or significant results from these experiments will be validated for mechanisms of action through functional wet-lab experiments using genetically modified bacteria or cell lines, depending on the nature of the results.

Overall, this study will further our understanding of TB and aid future drug, vaccine and diagnostic research targeting the global epidemic of TB.