Innate immunity to tuberculosis: a forward genetic approach (133.15)

Abstract

Abstract We have developed a forward genetic screen in the zebrafish to identify host genes that control resistance and susceptibility to tuberculosis. Using facile live imaging techniques to screen mutant larvae for alterations in the pathogenesis of Mycobacterium marinum, we have identified multiple genetic loci that alter myeloid development and functions, including macrophage microbicidal capacity, migration and aggregation. Through a positional cloning approach, we have identified genes affected by three mutations causing hypersusceptibility to M. marinum. One of these mutations lies in the gene encoding leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme that produces leukotriene B4 (LTB4). In spite of LTB4's role as a potent leukocyte chemoattractant, the mutant is not compromised in the initial migration of macrophages to the site of infection. Rather mutant macrophages are defective in limiting intracellular bacterial growth and are quickly killed by the infection. Chemical inhibitors of this pathway mimic the mutant phenotype. Finally, we show that the protective effect of LTA4H in limiting mycobacterial growth may be attributable to a role in the regulation of TNF, as mutant fish fail to induce TNF transcription in response to infection.