Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1.
Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1.
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DOI：
10.1038/gene.2008.68
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发表时间：
2009-01
影响因子：
5
通讯作者：
Kramnik, I.
中科院分区：
文献类型：
--
作者：
Sissons, J.;Yan, B-S;Pichugin, A. V.;Kirby, A.;Daly, M. J.;Kramnik, I.
结核病仍然是一个重大的全球健康问题：三分之一的人口感染结核分枝杆菌（MTB），其中10%的人一生都有患结核病的风险。虽然宿主的遗传变异在结核病感染的结果中的重要作用是有据可查的，但由于复杂的多基因控制和基因-环境相互作用的显著影响，免疫活性个体中易感性的遗传决定因素在很大程度上仍然未知。免疫活性近交系小鼠中宿主对MTB的抗性的天然遗传变异反映了人类之间的异质性，并允许使用小鼠模型逐步解剖遗传控制。以前，我们的特点是小鼠的超易感性位点（sst 1）和定位额外的数量性状位点（QTL）控制抗结核免疫，其中7号染色体上的QTL是最突出的。在这项研究中，我们解决了一个特定的作用，染色体7 QTL，并发现，染色体7和sst 1位点独立控制不同的机制，主机抗结核病，但表型表达的染色体7位点的显着影响与sst 1的相互作用。虽然sst 1基因座在肺中特别重要，7号染色体基因座的作用是系统性的，但这两个基因座都影响巨噬细胞介导的体内毒性MTB控制。它们的综合作用占敏感和抗性亲本菌株之间存活率显著差异的一半。进一步的7号染色体基因座的遗传和功能解剖，以确定致病的遗传变异，将有助于解开结核病易感性的免疫功能正常的主机的遗传基础。
Tuberculosis remains a significant global health problem: one-third of the human population is infected with Mycobacterium tuberculosis (MTB) and 10% of those are at lifetime risk of developing tuberculosis. Although an important role of genetic variation of host in outcomes of tuberculosis infection is well documented, genetic determinants of susceptibility in immunocompetent individuals remain largely unknown due to complex multigenic control and significant impact of genes - environment interactions. Natural genetic variation of host resistance to MTB in immunocompetent inbred mice reflects heterogeneity among humans and allows stepwise dissection of the genetic control using a mouse model. Previously we characterized a mouse super-susceptibility locus (sst1) and mapped additional quantitative trait loci (QTLs) controlling anti-tuberculosis immunity, among which a QTL on chromosome 7 was most prominent. In this study we addressed a specific role of the chromosome 7 QTL and found that the chromosome 7 and sst1 loci independently control distinct mechanisms of host resistance to MTB, but the phenotypic expression of the chromosome 7 locus is significantly influenced by interactions with the sst1. While the sst1 locus is especially important in the lungs and the effect of the chromosome 7 locus is systemic, both loci affect macrophage-mediated control of virulent MTB in vivo. Their combined effect accounts for half of the dramatic difference in survival between the susceptible and resistant parental strains. Further genetic and functional dissection of the chromosome 7 locus to identify causal genetic variation will help untangle the genetic basis of tuberculosis susceptibility in immunocompetent hosts.
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影响因子：
64.5
作者：
SCHEFFNER, M;HUIBREGTSE, JM;HOWLEY, PM
通讯作者：
HOWLEY, PM
DOI：
10.1073/pnas.150227197
发表时间：
2000-07-18
影响因子：
11.1
作者：
Kramnik, I;Dietrich, WF;Bloom, BR
通讯作者：
Bloom, BR
影响因子：
11.1
作者：
Schurr, E.
通讯作者：
Schurr, E.
影响因子：
6.4
作者：
Lavebratt, C;Apt, AS;Schurr, E
通讯作者：
Schurr, E
影响因子：
3.1
作者：
KROG, HH;MOUTIER, R
通讯作者：
MOUTIER, R