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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • March 5, 2010

Published In

Volume / Issue

  • 140 / 5

Start / End Page

  • 717 - 730

PubMed ID

  • 20211140

Pubmed Central ID

  • 20211140

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2010.02.013

Language

  • eng

Conference Location

  • United States