Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia.
Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia.
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不同的细菌基因表达模式和减弱的宿主免疫反应与持续耐甲氧西林抗甲氧西葡萄球菌金黄色葡萄球菌菌血症期间低水平万古霉素耐药性的演变有关。
DOI：
10.1186/1471-2180-8-39
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发表时间：
2008-02-27
期刊：
影响因子：
4.2
通讯作者：
Davies, John K.
中科院分区：
文献类型：
--
作者：
Howden, Benjamin P.;Smith, Danielle J.;Mansell, Ashley;Johnson, Paul D. R.;Ward, Peter B.;Stinear, Timothy P.;Davies, John K.
金黄色葡萄球菌（万古霉素中间体S。金黄色葡萄球菌（VISA）和异源VISA [hVISA]）在持续感染和万古霉素治疗失败期间出现。与“细胞壁刺激子”相关的基因的上调和vraSR操纵子中的突变都与抗性的发展有关，然而抗性的分子机制尚未完全理解。为了进一步阐明导致耐药的机制，使用多个临床对的万古霉素敏感的S.金黄色葡萄球菌（VSSA）和hVISA/VISA（n = 5），以及三个VSSA对照对，其来自没有发展hVISA/VISA的患有持续性菌血症的住院患者。基于转录组结果，对多个基因进行测序，并在VSSA和hVISA/VISA对中评估先天免疫系统刺激。在这里，我们表明，上调vraS和“细胞壁刺激子”是不是必不可少的收购低水平的万古霉素耐药性和不同的转录反应发生，甚至密切相关的hVISA/VISA菌株之间。vraSR、saeSR、mgrA、rot和merR调节基因和上游区域的DNA测序并未显示VSSA和hVISA/VISA之间存在任何差异，尽管转录变化表明这些基因座的突变可能与这些菌株的耐药性有关。通过独立的生物测定证实了hVISA/VISA中增强的胶囊产生和降低的蛋白A表达，并完全支持转录组数据。在持续菌血症期间保持万古霉素敏感的三对对照组中未观察到这些变化。在巨噬细胞感染模型中，hVISA/VISA菌株中细胞表面结构的变化与NF-κB活化显著降低相关，导致TNF-α和IL-1β表达降低。我们的结论是，有多种途径，以低水平的万古霉素耐药的链球菌。金黄色葡萄球菌，甚至在密切相关的临床菌株中，并且这些可以导致减弱的宿主免疫应答。与hVISA/VISA菌株相关的持续感染可能是宿主病原体相互作用变化以及抗生素敏感性降低的结果。
Low-level vancomycin resistance in Staphylococcus aureus (vancomycin-intermediate S. aureus (VISA) and hetero-VISA [hVISA]) emerges during persistent infection and failed vancomycin therapy. Up-regulation of genes associated with the "cell wall stimulon" and mutations in the vraSR operon have both been implicated in the development of resistance, however the molecular mechanisms of resistance are not completely understood. To further elucidate the mechanisms leading to resistance transcriptome comparisons were performed using multiple clinical pairs of vancomycin-susceptible S. aureus (VSSA) and hVISA/VISA (n = 5), and three VSSA control pairs from hospitalized patients with persistent bacteraemia that did not develop hVISA/VISA. Based on the transcriptome results multiple genes were sequenced and innate immune system stimulation was assessed in the VSSA and hVISA/VISA pairs. Here we show that up-regulation of vraS and the "cell wall stimulon" is not essential for acquisition of low-level vancomycin resistance and that different transcriptional responses occur, even between closely related hVISA/VISA strains. DNA sequencing of vraSR, saeSR, mgrA, rot, and merR regulatory genes and upstream regions did not reveal any differences between VSSA and hVISA/VISA despite transcriptional changes suggesting mutations in these loci may be linked to resistance in these strains. Enhanced capsule production and reduced protein A expression in hVISA/VISA were confirmed by independent bioassays and fully supported the transcriptome data. None of these changes were observed in the three control pairs that remained vancomycin-susceptible during persistent bacteremia. In a macrophage model of infection the changes in cell surface structures in hVISA/VISA strains were associated with significantly reduced NF-κB activation resulting in reduced TNF-α and IL-1β expression. We conclude that there are multiple pathways to low-level vancomycin resistance in S. aureus, even among closely related clinical strains, and these can result in an attenuated host immune response. The persistent infections associated with hVISA/VISA strains may be a consequence of changes in host pathogen interactions in addition to the reduced antibiotic susceptibility.
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DOI：
10.1016/s1473-3099(01)00091-3
发表时间：
2001-10-01
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Hiramatsu, K
通讯作者：
Hiramatsu, K
DOI：
10.1006/bbrc.2000.2277
发表时间：
2000-03-16
影响因子：
3.1
作者：
Kuroda, M;Kuwahara-Arai, K;Hiramatsu, K
通讯作者：
Hiramatsu, K
影响因子：
3.2
作者：
McAleese, F;Wu, SW;Tomasz, A
通讯作者：
Tomasz, A
影响因子：
4.9
作者：
Boyle-Vavra, S;Berke, SK;Daum, RS
通讯作者：
Daum, RS
影响因子：
11.8
作者：
Howden, BP;Ward, PB;Grayson, ML
通讯作者：
Grayson, ML