A Global Virulence Regulator in Acinetobacter baumannii and Its Control of the Phenylacetic Acid Catabolic Pathway
A Global Virulence Regulator in Acinetobacter baumannii and Its Control of the Phenylacetic Acid Catabolic Pathway
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DOI：
10.1093/infdis/jiu024
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发表时间：
2014-07-01
影响因子：
6.4
通讯作者：
Peleg, Anton Y.
中科院分区：
文献类型：
--
作者：
Cerqueira, Gustavo M.;Kostoulias, Xenia;Peleg, Anton Y.
背景鲍曼不动杆菌是最臭名昭著的医院获得性病原体之一，迫切需要新的治疗策略。双组分调节系统代表了潜在的治疗靶点，因为它们介导微生物适应不断变化的环境，通常控制毒力，并且对细菌具有特异性。在这里，我们描述了第一个全球毒力调节器在A。方法和结果。利用转录谱分析和功能测定的缺失突变体在A。鲍曼不动杆菌传感器激酶基因A1S_0574（称为gacS），我们表明该传感器激酶调节关键的毒力特征，包括皮利合成、生物膜和运动性，导致哺乳动物败血症模型中的毒力减弱。值得注意的是，我们还确定了GacS调节一个操纵子新的A。鲍曼不动杆菌（PAA操纵子），其负责芳香族化合物的代谢。paaE（A1S_1340）的缺失证实了该操纵子在A.鲍曼不动杆菌毒力最后，我们鉴定了GacS的同源反应调节子（A1S_0236），并证实了它们的相互作用。A1S_0236显示调节75%的GacS转录组和相同的毒力表型。A1S_0236的过表达恢复了gacS突变体中的毒力。我们的研究描述了一种全球毒力调节因子，它可能在最麻烦的医院获得性病原体中提供替代治疗靶点。
Background. Acinetobacter baumannii is one of the most notorious hospital-acquired pathogens, and novel treatment strategies are desperately required. Two-component regulatory systems represent potential therapeutic targets as they mediate microorganism adaptation to changing environments, often control virulence, and are specific to bacteria. Here we describe the first global virulence regulator in A. baumannii.Methods and Results. Using transcriptional profiling and functional assays of a deletion mutant in the A. baumannii sensor kinase gene, A1S_0574 (termed as gacS), we show that this sensor kinase regulates key virulence characteristics, including pili synthesis, biofilms, and motility, resulting in virulence attenuation in a mammalian septicemia model. Notably, we also identified that GacS regulates an operon novel to A. baumannii (paa operon), which is responsible for the metabolism of aromatic compounds. Deletion of paaE (A1S_1340) confirmed the role of this operon in A. baumannii virulence. Finally, we identified the cognate response regulator (A1S_0236) for GacS and confirmed their interaction. A1S_0236 was shown to regulate 75% of the GacS transcriptome and the same virulence phenotypes. Overexpression of A1S_0236 restored virulence in the gacS mutant.Conclusions. Our study characterizes a global virulence regulator, which may provide an alternate therapeutic target, in one of the most troublesome hospital-acquired pathogens.