Identify and Treating the Cause of Tuberculosis Immunopathology

• PhD and Graduate Research Masters

Transmitted by aerosol, M. tuberculosis causes a chronic infection which can persist for years without developing into disease; or for roughly 5-15% of infected people, and 10 million people annually, it develops into a chronic inflammatory disease, destroying the architecture of the organ it infects. We are particularly interested in the different ways M. tuberculosis manipulates programmed cell death pathways to promote its survival and cause inflammatory host cell death to destroy the lung and other sites of infection, allowing the bacteria to spread and cause disease.

Our analysis of whole blood transcriptional and epigenetic signatures from TB patients, and those co-infected with HIV and COVID-19 has identified the role of multiple cell death pathways in TB risk, particularly pyroptosis, apoptosis and extracellular trap formation. The student will use a combination of clinical pathogen variants, primary human and induced pluripotent stem cell culture, CRISPR/Cas, advanced imaging, transcriptomic and proteomic techniques to characterise inflammatory cell death pathways and identify inhibitors to develop into new preventative treatments for TB.

Our research focuses on how epidemiological risk factors, such as undernutrition, age and sex differences, and viral co-infections, particularly HIV-1 and SARS-CoV-2 increase tuberculosis (TB) risk. We study how the response of innate immune cells which engulf the tuberculosis bacteria, namely macrophages and neutrophils, is dysregulated by these risk factors leading to TB disease development. We combine analysis of clinical cohort samples to identify novel pathways of pathogenesis in humans, with in vitro infection models to determine the molecular mechanism underlying disease risk. Together this enables us to identify novel therapeutic targets and develop diagnostic biomarkers to improve earlier TB diagnosis and inform who will most benefit from treatment.

We achieve this using a range of cutting-edge techniques to interrogate genetic, epigenetic, transcriptomic and proteomic changes in both the host and bacteria to identify how these impact the inflammatory response during infection. We are particularly interested in regulation of cell death pathways and the heterogeneity of cellular responses due to tissue micro-environmental changes which we probe using single cell omics, spatial omics and advanced live cell imaging techniques.