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The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.

Publication ,  Journal Article
Tobin, DM; Vary, JC; Ray, JP; Walsh, GS; Dunstan, SJ; Bang, ND; Hagge, DA; Khadge, S; King, M-C; Hawn, TR; Moens, CB; Ramakrishnan, L
Published in: Cell
March 5, 2010

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

March 5, 2010

Volume

140

Issue

5

Start / End Page

717 / 730

Location

United States

Related Subject Headings

  • Zebrafish
  • Tuberculosis
  • Leprosy
  • Humans
  • Genetic Predisposition to Disease
  • Fish Diseases
  • Epoxide Hydrolases
  • Disease Models, Animal
  • Developmental Biology
  • Animals
 

Citation

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Tobin, D. M., Vary, J. C., Ray, J. P., Walsh, G. S., Dunstan, S. J., Bang, N. D., … Ramakrishnan, L. (2010). The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell, 140(5), 717–730. https://doi.org/10.1016/j.cell.2010.02.013
Tobin, David M., Jay C. Vary, John P. Ray, Gregory S. Walsh, Sarah J. Dunstan, Nguyen D. Bang, Deanna A. Hagge, et al. “The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.Cell 140, no. 5 (March 5, 2010): 717–30. https://doi.org/10.1016/j.cell.2010.02.013.
Tobin DM, Vary JC, Ray JP, Walsh GS, Dunstan SJ, Bang ND, et al. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell. 2010 Mar 5;140(5):717–30.
Tobin, David M., et al. “The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.Cell, vol. 140, no. 5, Mar. 2010, pp. 717–30. Pubmed, doi:10.1016/j.cell.2010.02.013.
Tobin DM, Vary JC, Ray JP, Walsh GS, Dunstan SJ, Bang ND, Hagge DA, Khadge S, King M-C, Hawn TR, Moens CB, Ramakrishnan L. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell. 2010 Mar 5;140(5):717–730.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

March 5, 2010

Volume

140

Issue

5

Start / End Page

717 / 730

Location

United States

Related Subject Headings

  • Zebrafish
  • Tuberculosis
  • Leprosy
  • Humans
  • Genetic Predisposition to Disease
  • Fish Diseases
  • Epoxide Hydrolases
  • Disease Models, Animal
  • Developmental Biology
  • Animals