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
-
- Tuberculosis/genetics*
- Tuberculosis/immunology
- Zebrafish
- Epoxide Hydrolases/genetics*
- Animals
- Disease Models, Animal
- Leprosy/genetics*
- Leprosy/immunology
- Humans
- Genetic Predisposition to Disease
- Fish Diseases/genetics*
- Fish Diseases/immunology
- PubMed
- 20211140 Full text @ Cell
Citation
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. (2010) The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans. Cell. 140(5):717-730.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping