The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.
The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.
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DOI：
10.1016/j.cell.2010.02.013
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发表时间：
2010-03-05
期刊：
影响因子：
64.5
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Tobin DM;Vary JC Jr;Ray JP;Walsh GS;Dunstan SJ;Bang ND;Hagge DA;Khadge S;King MC;Hawn TR;Moens CB;Ramakrishnan L
暴露于结核分枝杆菌产生不同的早期结果，从耐药性感染到疾病进展。在这里，我们报告的结果，从一个前向遗传筛选斑马鱼幼虫，确定多个突变类与不同模式的先天易感性海洋分枝杆菌。一种过敏突变体定位于编码白三烯A4水解酶的lta4h基因座，该酶催化白三烯B4（LTB 4）合成的最后一步，LTB 4是一种有效的化学引诱剂和促炎性类花生酸。lta4h突变通过将类花生酸底物重定向为抗炎脂氧素而赋予不依赖于LTB4减少的过敏性。所产生的抗炎状态通过限制肿瘤坏死因子的产生而允许增加分枝杆菌增殖。在人类中，我们发现结核病和多杆菌麻风病的保护与LTA4H多态性的杂合性有关，而LTA4H多态性以前与LTB4的差异产生有关。我们的研究结果表明，在脊椎动物抵抗分枝杆菌感染的平衡类花生酸生产保守的作用。
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-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 LTB4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
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DOI：
10.1084/jem.20080767
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen M;Divangahi M;Gan H;Shin DS;Hong S;Lee DM;Serhan CN;Behar SM;Remold HG
通讯作者：
Remold HG
影响因子：
30.8
作者：
Helgadottir, A;Manolescu, A;Stefansson, K
通讯作者：
Stefansson, K
影响因子：
158.5
作者：
Keane, J;Gershon, S;Braun, MM
通讯作者：
Braun, MM
影响因子：
15.3
作者：
Cobat, Aurelie;Gallant, Caroline J.;Alcais, Alexandre
通讯作者：
Alcais, Alexandre
影响因子：
3.6
作者：
Hardwick, C.;White, D.;Lipman, M.
通讯作者：
Lipman, M.