Susceptibility to tuberculosis:: A locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs
Susceptibility to tuberculosis:: A locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs
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DOI：
10.1073/pnas.1031727100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Gros, P
中科院分区：
文献类型：
--
作者：
Mitsos, LM;Cardon, LR;Gros, P
小鼠DBA/2（D2）菌株对毒性结核分枝杆菌感染非常敏感，而C57 BL/6（B6）更具抗性。用M.肺结核H37 Rv通过呼吸途径的复制是双相的：在前3周期间，两种菌株的肺中都有快速的细菌生长，而超过这一点，复制在B6中停止，但在D2中继续，导致迅速致命的肺部疾病。目的：筛选出M.在这两个菌株的肺中，98只提供信息的（B6 × D2）F-2小鼠通过呼吸途径感染M.结核病H37 Rv（2 × 10（2）菌落形成单位），90天时肺中细菌复制的程度被用作全基因组扫描中易感性的定量测量。数量性状基因座作图确定了19号染色体上的一个主要基因座（结核病抗性基因座-4，Trl-4;优势比对数5.6），该基因座调节M.结核病和占25%的表型变异。Trl-4的B6等位基因以不完全显性方式遗传，并与细菌复制减少相关。一个基因座（Trl-3）的额外作用，以前显示影响静脉内感染M.肺结核也被发现。在Trl-3和Trl-4处对B6等位基因纯合的F2小鼠与B6亲本一样具有抗性，而对D2等位基因纯合的小鼠与D2亲本一样易感。这些结果表明Trl-3和Trl-4在调节M.结核
The mouse DBA/2 (D2) strain is very susceptible to infection with virulent Mycobacterium tuberculosis, whereas C57BL/6 (B6) is much more resistant. Infection of D2 and B6 mice with M. tuberculosis H37Rv by the respiratory route is biphasic: during the first 3 weeks, there is rapid bacterial growth in the lung of both strains, whereas beyond this point replication stops in B6 but continues in D2, causing rapidly fatal pulmonary disease. To identify the genes regulating growth of M. tuberculosis in the lungs of these two strains, 98 informative (B6 x D2) F-2 mice were infected by the respiratory route with M. tuberculosis H37Rv (2 x 10(2) colony-forming units), and the extent of bacterial replication in the lungs at 90 days was used as a quantitative measure of susceptibility in a whole-genome scan. Quantitative trait locus mapping identified a major locus on chromosome 19 (Tuberculosis resistance locus-4, Trl-4; logarithm of odds 5.6), which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. B6 alleles at Trl-4 were inherited in an incompletely dominant fashion and associated with reduced bacterial replication. An additional effect of a locus (Trl-3), previously shown to affect survival to i.v. infection with M. tuberculosis, was also noted. F2 mice homozygous for B6 alleles at both Trl-3 and Trl-4 were as resistant as B6 parents, whereas mice homozygous for D2 alleles were as susceptible as D2 parents. These results suggest a strong genetic interaction between Trl-3 and Trl-4 in regulating pulmonary replication of M. tuberculosis.