Tuberculosis bacteria hijack the immune system's own cells to spread through the body, and a zebrafish model is revealing exactly how they do it. The problem: Tuberculosis kills over a million people each year, and the only vaccine is a century old. Researchers have long assumed that the granuloma—the clump of immune cells that forms around TB bacteria—is the body's way of walling off the infection. This lab discovered the opposite: the granuloma actually helps the bacteria expand and spread. A bacterial protein called ESAT6 triggers nearby cells to release a signal that recruits fresh macrophages to the site, where they become infected. The researchers will now dissect each step of this process in zebrafish, using biochemical and genetic tools. They will also screen hundreds of mutant zebrafish to find genes that make animals more or less susceptible to infection. One such screen already identified the leukotriene B4 pathway, which led to new ideas for TB treatments. If this fundamental science succeeds, it could reveal entirely new drug targets—molecules the bacteria rely on to manipulate the immune response. That would be a shift from decades of TB drug development focused on killing the bacterium itself.
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My laboratory pioneered the zebrafish-Mycobacterium marinum model of tuberculosis to make surprising discoveries about tuberculosis with profound clinical implications. We will pursue these discoveries and approaches: 1. Mycobacterial entry: We will pursue our new findings that mycobacteria manipulate host macrophages at the site of entry to their advantage. 2. The tuberculous granuloma: We have found the granuloma, the hallmark structure of TB long thought to be a critical host protective structure, actually promotes bacterial expansion and dissemination. A bacterial virulence factor ESAT6 promotes macrophage migration to the growing granuloma through MMP9 induction neighboring epithelial cells, combined with death of infected macrophages. The arriving macrophages phagocytose dying infected macrophages, thus becoming infected and providing mycobacteria with new replication niches. We will pursue a detailed understanding of each of these steps. - How does ESAT6 induce MMP9 in epithelial cells? - How does MMP9 induce macrophage chemotaxis? - How do arriving macrophages find, and phagocytose dying macrophages? We will take biochemical, pharmacological and in vivo approaches to fully dissect these pathways. 3. Zebrafish mutant screen: Our pilot zebrafish mutant screen identified the leukotriene B4 synthesis pathway to play a complex role in human TB through modulation of inflammation. This understanding has led to new therapeutic possibilities. We will join an ong oing comprehensive zebrafish mutant phenotype screen at the Sanger Centre to gather a comprehensive zebrafish mutant library with altered susceptibility to M. marinum. We will understand the mechanisms of their altered susceptibility.
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