1. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans
- Author
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Deanna A. Hagge, Thomas R. Hawn, Jay C. Vary, Nguyen Duc Bang, Saraswoti Khadge, Gregory S. Walsh, David M. Tobin, John P. Ray, Sarah J. Dunstan, Mary Claire King, Lalita Ramakrishnan, and Cecilia B. Moens
- Subjects
HUMDISEASE ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Microbiology ,Mycobacterium tuberculosis ,Fish Diseases ,03 medical and health sciences ,0302 clinical medicine ,Leprosy ,Animals ,Humans ,Tuberculosis ,Genetic Predisposition to Disease ,MOLIMMUNO ,Zebrafish ,Mycobacterium marinum ,030304 developmental biology ,Epoxide Hydrolases ,0303 health sciences ,Leukotriene ,Innate immune system ,Biochemistry, Genetics and Molecular Biology(all) ,biology.organism_classification ,3. Good health ,Disease Models, Animal ,Immunology ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,Eicosanoid Production ,Genetic screen - Abstract
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) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) 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 LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
- Published
- 2010