Innate immunity and inflammation in tuberculosis: insights from the zebrafish and therapeutic opportunities

Despite > 60-years of antitubercular chemotherapies, tuberculosis (TB) has been the leading infectious cause of death. My laboratory pioneered the zebrafish - Mycobacterium marinum tuberculosis model to better understand TB pathogenesis. It enabled surprising discoveries about tuberculosis with immediate implications for new therapeutic modalities.

Here, we will use the zebrafish to discover genetic alterations that impact upon immunity and inflammation in early TB. This will uncover human genetic susceptibilities to tuberculosis and druggable pathways underlying them. Our key goals are to: - Map and characterize hypersusceptible zebrafish mutants identified in a forward genetic screen.

We will identify their causative lesions and characterize which infection step is altered in them and how, so as to understand how these genes modulate infection. - Identify gene-regulatory networks involved in early granuloma formation.

RNA-seq analyses will provide a blueprint of gene expression changes associated with tuberculous granuloma formation, which we will link dynamically and functionally to the individual processes involved to determine their consequences. - Determine mechanisms of human primary immunodeficiencies to mycobacterial infections using the zebrafish.

We will model in the zebrafish known human genetic mutations that increase human susceptibility to mycobacterioses to determine their susceptibility mechanisms, particularly in early infection.