Tuberculosis (TB) is the leading cause of global infectious mortality. Mycobacterium tuberculosis establishes 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 that destroys the architecture of the organ it infects. It does this by manipulating programmed cell death pathways of the cells it infects and of neighbouring cells, to allow it to persist and evade being killed by immune cells that are recruited in to help kill it. This inflammatory host cell death slowly destroys the lung and other sites of infection, ultimately allowing the bacteria to escape into airways so it can complete its transmission cycle.
Our team have undertaken large scale clinical studies of recent tuberculosis contacts in South Africa to identify the immunological pathways that are dysregulated in those who develop tuberculosis, compared to those able to control infection. Our analysis of whole blood transcriptional and epigenetic signatures from these individuals has identified the role of multiple cell death pathways in TB risk, particularly pyroptosis, necroptosis, apoptosis and extracellular trap formation.
The student will use a combination of clinical M. tuberculosis variants, primary human and induced pluripotent stem cell culture, CRISPR/Cas, advanced imaging, transcriptomic, proteomic and flow cytometry techniques to characterise immune population-specific cell death pathway manipulation by M. tuberculosis and identify and leverage small molecule therapeutics to shift programmed cells death from a chronic inflammatory to a protective clearing response. Animal model systems approaches will be used to demonstrate that therapeutic clearance provides long-term protective cure from subsequent disease.
