We aim to extend current understanding of host determinants of protection and pathogenesis in immune-mediated disease, with a principal focus on tuberculosis (TB). Ultimately, this will inform development of novel therapeutic strategies, improved vaccines and new diagnostic tools. We combine transcriptomic profiling of human TB samples with the zebrafish Mycobacterium marinum infection model of TB, to study factors that calibrate an effective immune response, able to control bacterial growth without pathology (MRC Clinician Scientist Fellowship). We developed a novel bioinformatic approach to identify drivers of variable human immune responses correlated with TB severity, which suggests Type I interferon responses may be protective. We are currently testing whether genetic manipulation of levels of selected Type I interferon pathway components impacts disease severity in zebrafish larval mycobacterial infection, using CRISPR genome editing to model gene deficiency. More recently we exploited single-cell transcriptome and T cell receptor (TCR) repertoire profiling of bronchoalveolar cells to study the immune pathogenesis of post-COVID lung disease (BRC grant). We found marked clustering of related TCRs from multiple donors, suggestive of antigen-specific T cell responses to tissue-localised epitopes. Lack of enrichment for SARS-CoV-2-specific TCRs suggests T cell-mediated immunopathology arising from failure of immunological tolerance to self-antigens. Our data suggest therapies targeting T cells may have a role in preventing lung tissue damage following SARS-CoV-2 infection. In future we aim to expand our focus beyond respiratory infection and take advantage of the fact that zebrafish larvae provide a model to study innate immune responses in isolation. We aim to identify and validate the principal drivers of innate immune response pathways that affect the outcome of diverse infectious and inflammatory diseases. We will adopt innate immune skin challenge models in healthy people and test genes that drive variation in human cell type-specific innate immune responses in a range of zebrafish inflammation models.