Tuberculosis (TB) is a chronic granulomatous disease due to Mycobacterial tuberculosis (Mtb) infection, and among the commonest microbial causes of mortality. World-wide, there are approximately 10 million new cases of TB and 1.5 million deaths attributable to TB per year. TB can affect anyone, but it is the commonest cause of death in people living with HIV (PLWH). However, most people who become infected with Mtb do not develop disease. We still do not understand whey some people develop disease. Variation in immune response to infection is thought to be important. Therefore, identification of immune determinants of protection and pathogenesis in tuberculosis remains a global research priority.

In an collaboration with the Africa Health Research Institute , we are using cutting-edge methodology to comprehensively detail perturbation of in vivo human Mtb-reactive T cell responses in this group, independent of total T cell counts. We will test the hypothesis that dominant Mtb-reactive T cells in ART-treated PLWH have restricted clonality, target different antigens and exhibit different functionality, compared to those of HIV-negative individuals. We will identify which of these T cell traits impact on macrophage control of Mtb-growth, and predict disease-risk in multiple independent cohorts sampled from the general population. We expect our findings to drive innovations in vaccine development and evaluation, personalised risk-stratification to enable precision targeting of preventative antimicrobial treatment, and development of immunomodulatory therapies for disease.