02053nas a2200373   4500000000100000008004100001260001600042653001200058653002700070653002300097653001800120653003800138653001100176653001200187653001700199653001400216100001300230700001100243700001000254700001200264700001500276700001100291700001200302700001300314700001100327700001200338700001200350700001900362245009700381300001100478490000800489520116800497022001401665       2010                            d  c2010 Mar 0510aAnimals10aDisease Models, Animal10aEpoxide Hydrolases10aFish Diseases10aGenetic Predisposition to Disease10aHumans10aleprosy10aTuberculosis10aZebrafish1 aTobin DM1 aVary J1 aRay J1 aWalsh G1 aDunstan SJ1 aBang N1 aHagge D1 aKhadge S1 aKing M1 aHawn TR1 aMoens C1 aRamakrishnan L00aThe lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.  a717-300 v1403 a<p>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.</p>  a1097-4172