Journal article
The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans
DM Tobin, JC Vary, JP Ray, GS Walsh, SJ Dunstan, ND Bang, DA Hagge, S Khadge, MC King, TR Hawn, CB Moens, L Ramakrishnan
Cell | CELL PRESS | Published : 2010
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 A4 hydrolase, which catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflam..
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Awarded by W. M. Keck Foundation
Funding Acknowledgements
We thank D. Payan for suggesting the zebrafish; J. Bennett and C.B. Wilson for encouragement and help in obtaining zebrafish facilities; C.N. Serhan for advice on eicosanoids; K. Winglee for developing FPC analysis; A. Carmany- Rampey, P. Grant, and C. Miller for setting up early pressure screens; R. Kim and D. Beery for assistance with microinjections; J. Cameron and L. Swaim for fish husbandry; H. Clay for the tnf/fms image; and A. Huttenlocher for the mpo antibody. For the human studies, we gratefully acknowledge all participants and the clinical staff of the Hospital of Tropical Diseases (particularly T.T.H. Chau and G. Thwaites), Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease (particularly N.H. Dung, N.T.B. Yen and N.T.N. Lan), and Hung Vuong Obstetric Hospital (N.T. Hieu) for facilitating the patient sample collection, M. Janer and S. Li for DNA genotyping, and M. K. Lee for statistical advice. This work was supported by the Burroughs Wellcome Fund (L.R. and T.R.H.), the Akibene Foundation and the Keck Foundation (L.R.), the National Institutes of Health (L.R. and M.C.K.), an American Cancer Society Postdoctoral Fellowship and National Institutes of Health Bacterial Pathogenesis Training Grant (D.M.T.), the Odland Endowment of the University of Washington, Dermatology Foundation Dermatologist Investigator Research Fellowship, National Institutes of Health National Research Service Award, and the American Skin Association (J.C.V.), the Human Frontiers Science Program (G.S.W.), the Dana Foundation (T.R.H. and S.J.D.), the Heiser Program for Research in Tuberculosis and Leprosy (T.R.H.), the Wellcome Trust of Great Britain (S.J.D.) and the Leprosy Mission International (D.A.H.). C.B.M. is an investigator with the Howard Hughes Medical Institute. M.C.K. is an American Cancer Society Professor.