title: The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.
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.
authors.affiliation: Department of Microbiology, University of Washington, Box 357242, Seattle, WA 98195, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Tobin
authors.forename: Jay C
authors.initials: JC
authors.lastname: Vary
authors.forename: John P
authors.initials: JP
authors.lastname: Ray
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walsh
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dunstan
authors.forename: Nguyen D
authors.initials: ND
authors.lastname: Bang
authors.forename: Deanna A
authors.initials: DA
authors.lastname: Hagge
authors.forename: Saraswoti
authors.initials: S
authors.lastname: Khadge
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics*; D005393:Fish Diseases / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007918:Leprosy / Q000235:genetics* / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology; D015027:Zebrafish
chemical_list: D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase