PUBLICATION

The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans

Authors
Tobin, D.M., Vary, J.C. Jr, Ray, J.P., Walsh, G.S., Dunstan, S.J., Bang, N.D., Hagge, D.A., Khadge, S., King, M.C., Hawn, T.R., Moens, C.B., and Ramakrishnan, L.
ID
ZDB-PUB-100317-5
Date
2010
Source
Cell   140(5): 717-730 (Journal)
Registered Authors
Moens, Cecilia, Ramakrishnan, Lalita, Tobin, David, Walsh, Gregory
Keywords
MOLIMMUNO, HUMDISEASE
MeSH Terms
  • Animals
  • Disease Models, Animal
  • Epoxide Hydrolases/genetics*
  • Fish Diseases/genetics*
  • Fish Diseases/immunology
  • Genetic Predisposition to Disease
  • Humans
  • Leprosy/genetics*
  • Leprosy/immunology
  • Tuberculosis/genetics*
  • Tuberculosis/immunology
  • Zebrafish
PubMed
20211140 Full text @ Cell
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping