期刊
CELL
卷 140, 期 5, 页码 717-730出版社
CELL PRESS
DOI: 10.1016/j.cell.2010.02.013
关键词
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资金
- Burroughs Wellcome Fund
- Akibene Foundation
- Keck Foundation
- National Institutes of Health
- American Cancer Society Postdoctoral Fellowship
- National Institutes of Health Bacterial Pathogenesis Training
- Odland Endowment of the University of Washington
- American Skin Association
- Human Frontiers Science Program
- Dana Foundation
- Heiser Program for Research in Tuberculosis and Leprosy
- Wellcome Trust of Great Britain
- Leprosy Mission International
- Howard Hughes Medical Institute
Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B-4 (LTB4), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
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