Dynamics of Adaptive Microevolution of Hypermutable Pseudomonas aeruginosa during Chronic Pulmonary Infection in Patients with Cystic Fibrosis
Dynamics of Adaptive Microevolution of Hypermutable Pseudomonas aeruginosa during Chronic Pulmonary Infection in Patients with Cystic Fibrosis
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DOI：
10.1086/599360
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发表时间：
2009-07-01
影响因子：
6.4
通讯作者：
Hogardt, Michael
中科院分区：
文献类型：
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作者：
Hoboth, Christina;Hoffmann, Reinhard;Hogardt, Michael
背景在囊性纤维化（CF）患者中，高变铜绿假单胞菌的出现推动了对铜绿假单胞菌变体的选择，这些变体有效地适应了这些患者的发炎肺部。目的：详细研究慢性肺部感染CF患者铜绿假单胞菌生理学的适应性变化。我们进行了比较蛋白质组和转录组分析的连续，等基因分离恢复3-5年的时间从3个选定的CF患者。所分析的分离株包括甲基定向错配修复系统中具有高突变率和缺陷的分离株（以下称为“突变株”）和没有这种变化的分离株（以下称为“非突变株”）。除了毒力减弱外，铜绿假单胞菌适应过程主要影响代谢途径。在从终末期CF肺病患者中回收的突变体分离株中，我们观察到参与脂肪酸和氨基酸代谢以及能量产生的基因或蛋白质转录物增加。特别令人感兴趣的是参与以下途径和过程的基因的表达增加：（1）厌氧甜菜碱-脱亚胺酶途径，（2）厌氧呼吸（例如，例如，在一个实施例中，硝酸盐摄取蛋白OprF、天青蛋白和细胞色素c551过氧化物酶）;（3）微氧呼吸（e.例如，在一个实施例中，细胞色素氧化酶CBB 3），和（4）三羧酸循环和乙醛酸分流。值得注意的是，厌氧调节基因anr的转录增加与ANR依赖基因的上调相关。这些变化表明CF患者肺部化脓性分泌物产生的营养和微需氧条件下生长所需的基因向组成型表达的适应性转变。此外，这些结果为铜绿假单胞菌在进行性CF肺病期间使用的持久性策略提供了重要线索。
Background. In patients with cystic fibrosis (CF), the emergence of hypermutable Pseudomonas aeruginosa drives the selection of P. aeruginosa variants that are efficiently adapted to the inflamed lungs of these patients.Objective. To provide a detailed survey of adaptive changes in the physiology of P. aeruginosa during chronic lung infection in patients with CF.Methods. We performed a comparative proteome and transcriptome analysis of sequential, isogenic isolates recovered over a period of 3-5 years from 3 selected patients with CF. The isolates analyzed included both those with high mutation rates and defects in their methyl-directed mismatch repair system (hereafter, "mutators") and those without such changes (hereafter, "nonmutators").Results. In addition to attenuation of virulence, the P. aeruginosa adaptation process predominantly affects metabolic pathways. In mutator isolates recovered from patients with end-stage CF lung disease, we observed increases in the transcripts of genes or proteins involved in the metabolism of fatty acids and amino acids and the generation of energy. Of particular interest is the increased expression of genes involved in the following pathways and processes: (1) the anaerobic arginine-deiminase pathway, (2) anaerobic respiration (e. g., nitrate-uptake protein OprF, azurin, and cytochrome c551 peroxidase), (3) microaerobic respiration (e. g., cytochrome oxidase cbb3), and (4) the tricarboxylic acid cycle and glyoxylate shunt. Strikingly, increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes.Conclusions. These changes indicate an adaptive shift toward constitutive expression of genes required for growth under the nutritional and microaerobic conditions created by suppurative secretions in the lungs of patients with CF. In addition, these results provide important clues about the persistence strategies used by P. aeruginosa during progressive CF lung disease.