Project title: Structural and functional characterisation of Mycobacterial virulence proteins that modulate host immune response
Summary: Tuberculosis is the leading cause for mortality by an infectious disease, currently infecting ~10 million people per year, and 1/3 develop a latent infection. Mycobacterium tuberculosis (MTB) continues to be a very successful intracellular pathogen, resisting host defences by several mechanisms including the modulation of host cell signalling pathways and co-opting proteasomal degradation pathways. The Mammalian Cell entry (Mce) proteins are emerging as a group that have a role to play in some of these immune modulating activities. Mce2E associates with mitogen-activated protein kinase (MAPK) signaling pathways in a non-canonical D motif (a MAPK-docking motif) -dependent manner, modulating cytokines to suppress innate immune response. Mce2E also interacts with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to suppress K-48 ubiquitination, which prevents proteasomal degradation leading to epithelial cell proliferation. Additionally, a secreted MTB virulence protein, PtpA (tyrosine phosphatase) manipulates the activity of TRIM-27, a host ubiquitin ligase that regulates innate immunity. In this project, we shall structurally and biochemically characterise the interplay of these interactions to extend our understanding of pathogen strategies for intracellular survival, which can be targeted in the future for host-directed antibacterial therapies.