TB remains the world’s greatest infectious killer despite a vaccine (BCG) for a century and effective antibiotics for 60 years. TB’s persistence over millennia in the face of major medical advances underscores the ability of Mycobacterium tuberculosis to evade and exploit host defences and antibiotics. We study basic mechanisms of TB pathogenesis and drug tolerance. We often use the zebrafish larval model of TB which we have developed, exploiting its optical transparency and genetic and pharmacological tractability to monitor infection in real-time. Through genetic screens, we have identified host susceptibility and resistance factors to TB and understanding their mechanistic basis. We have discovered how specific mycobacterial virulence determinants exploit specific host vulnerabilities at specific steps to cause disease. Mycobacteria infect macrophages and survive in these primary immune defense cells by subverting their endocytic trafficking and microbicidal mechanisms. We have identified several mechanisms. We have shown how mycobacteria alter macrophage differentiation, migration, and aggregation to induce the formation of granulomas, complex, organized immune structures and turn them into mycobacterium-making factories. Ultimately, mycobacteria can cause granuloma breakdown by inducing multiple modes of programmed macrophage death, which further increases bacterial growth and transmission to new hosts. We are discovering how mycobacteria become antibiotic-resistant by inducing their multiple drug efflux pumps.

Our findings have been borne out in human TB studies and are informing new treatment strategies. Simultaneously, we are uncovering fundamental biology, for instance in macrophage organellar cross-talk, migration, adhesion and death.

Several available projects on important questions about TB host-pathogen interactions and drug resistance present attractive opportunities for PhD students. These use a range of approaches – genetic, biochemical, structural and microscopical – and are suited to be tailored to the individual candidate’s scientific and technological interests.

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