Investigating T cell compromise of macrophage defence in tuberculosis (360G-Wellcome-225477_Z_22_Z)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, causes 1.4 million deaths worldwide annually. Host immune responses to Mtb can mediate both protection and pathology. Macrophages contribute to control of Mtb growth and T cell activation of macrophages can augment this. However, T cell responses can also contribute to TB pathology and the underlying mechanisms are incompletely understood. It has been observed that T cells can induce macrophage death in vitro. Our understanding of the mechanisms mediating this phenomenon, its impact on Mtb growth, and the extent to which it contributes to human immune responses to Mtb in vivo is incomplete. I will use in vitro models of Mtb infection in human cells to dissect the molecular mechanisms underlying T cell-induced macrophage death and novel flow cytometry assays to assess its effect on Mtb growth and whether this is modulated by targeting the pathways responsible. I will use single cell transcriptomic analysis to assess the human immune response to Mtb in vivo for the pathways identified. This will enhance our mechanistic understanding of immune protection and pathogenesis in TB, with the potential to identify novel targets for adjuvant treatment and refine our development of T cell targeting vaccines for TB.