Keller Christine, Hoffmann Reinhard, Lang Roland, Brandau Sven, Hermann Corinna, Ehlers Stefan
Molecular Infection Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany.
Infect Immun. 2006 Jul;74(7):4295-309. doi: 10.1128/IAI.00057-06.
Classical twin studies and recent linkage analyses of African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to infection. Two susceptible and two resistant mouse strains were aerogenically infected with 1,000 CFU of M. tuberculosis, and the regulation of gene expression was examined by Affymetrix GeneChip U74A array with total lung RNA 2 and 4 weeks postinfection. Four weeks after infection, 96 genes, many of which are involved in inflammatory cell recruitment and activation, were regulated in common. One hundred seven genes were differentially regulated in susceptible mouse strains, whereas 43 genes were differentially expressed only in resistant mice. Data mining revealed a bias towards the expression of genes involved in granulocyte pathophysiology in susceptible mice, such as an upregulation of those for the neutrophil chemoattractant LIX (CXCL5), interleukin 17 receptor, phosphoinositide kinase 3 delta, or gamma interferon-inducible protein 10. Following M. tuberculosis challenge in both airways or peritoneum, granulocytes were recruited significantly faster and at higher numbers in susceptible than in resistant mice. When granulocytes were efficiently depleted by either of two regimens at the onset of infection, only susceptible mice survived aerosol challenge with M. tuberculosis significantly longer than control mice. We conclude that initially enhanced recruitment of granulocytes contributes to susceptibility to tuberculosis.
经典双胞胎研究以及近期针对非洲人群的连锁分析表明，宿主遗传因素可能在结核分枝杆菌感染的易感性或抵抗力中发挥作用。为了确定相关候选基因并检验它们的因果关系，我们利用了结核病小鼠模型，因为近交系小鼠品系对感染的易感性也存在很大差异。用1000个结核分枝杆菌集落形成单位（CFU）对两个易感小鼠品系和两个抗性小鼠品系进行空气感染，并在感染后2周和4周，用Affymetrix GeneChip U74A芯片检测全肺RNA，以研究基因表达调控情况。感染4周后，共有96个基因受到调控，其中许多基因参与炎症细胞的募集和激活。107个基因在易感小鼠品系中存在差异调控，而43个基因仅在抗性小鼠中差异表达。数据挖掘显示，易感小鼠中参与粒细胞病理生理学的基因表达存在偏差，例如中性粒细胞趋化因子LIX（CXCL5）、白细胞介素17受体、磷酸肌醇激酶3δ或γ干扰素诱导蛋白10等基因上调。在气道或腹膜受到结核分枝杆菌攻击后，易感小鼠中粒细胞的募集速度明显更快，数量也更多。在感染开始时，通过两种方案之一有效清除粒细胞后，只有易感小鼠在接受结核分枝杆菌气溶胶攻击后存活时间明显长于对照小鼠。我们得出结论，最初增强的粒细胞募集导致了对结核病的易感性。
