Characterising Mycobacterium tuberculosis in the human lung; developing new tools for antimicrobial drug discovery through the SH-TBL clinical trial

Tuberculosis (TB) remains a considerable socio-economic and health problem. TB is among the top ten causes of death worldwide and the leading cause of death by an infectious agent. 1.8 million people died from TB in 2015 and more than 2 billion people are latently infected. The problem is exacerbated by the emergence of multiple-drug resistant (MDR-TB) and extensively-drug resistant (XDR-TB) disease. The World Health Organisation End-TB strategy depends on the introduction of new tools, such as novel drug therapies, vaccines and diagnostics by 2025 to succeed. This cannot be achieved with current methodologies and development pipelines. Currently, no in vitro model is able to reproduce the localised microenvironments and granulomas of the tuberculous lung and the most widely-used animal model, the mouse, does not share this pathology. Thus, in vitro and many animal models for TB do not mimic conditions of the human lung and therefore have limited power to predict the efficacy of new drugs in patients. This has created a bottleneck where novel vaccine and drug candidates are not followed up due to the limited usefulness and scalability of animal models. New models rooted in the host-pathogen dynamic of the human tuberculous lung will be more representative of human disease and therefore more useful to the development of novel interventions. Such innovative clinically-relevant models will replace some animal models in early drug discovery programmes. This timely and original project will use molecular profiling tools to characterise Mycobacterium tuberculosis (M.tb) in lung tissue from TB patients undergoing lung resection surgery. Lung resection remains a treatment option for TB, this discard tissue is being collected in an ongoing clinical trial (SH-TBL) to understand the immunology of TB lung lesions. This project, working alongside the clinical trial, will identity novel TB vaccine candidates expressed at the site of pathology, where vaccines and drugs are targeted, and develop a model using insights from both M.tb phenotype and lung lesion immunology to replace animals in early TB drug discovery research. This project will also demonstrate that human tissue can provide an ethical, viable and superior alternative to animal models for human infectious disease research and has the potential to replace experiments currently conducted in a range of laboratory animals.