Human tuberculosis granulomas as targets for host-directed therapies and prediction of disease progression

Tuberculosis (TB) is a bacterial disease that is responsible for 1.5 million deaths every year. The problem is worsened by increasing numbers of patients responding poorly to current standard treatment. There is an urgent need for new treatment and diagnostic tools. TB disease progression is characterised by a combination of bacterial growth and immune-mediated lung damage. Typically, lung damage is characterised by dissociation of granulomas, which are complex cellular structures that restrict bacteria. However, granulomas can develop caseum, a key feature of lung damage. Inhibition of factors associated with granuloma caseation presents an attractive area for discovery of drugs that can limit tissue destruction.

In our recent work, we demonstrated that proteomics can be used to determine events that shape a TB granuloma. We also found that important factors required for TB granuloma development are regionally distributed, with pro-inflammatory proteins enriched in the caseum. We will investigate proteins that are associated with caseum formation and tissue damage and develop host-directed therapies to decrease the damage. We will also characterise macrophage functional diversity in granulomas and develop predictive biomarkers that can be used to diagnose those at highest risk for caseation.

Our findings will help improve TB treatments.

This grant was awarded under the scheme's previous name of Intermediate Fellowships in Public Health and Tropical Medicine.