The quorum sensing volatile molecule 2-amino acetophenon modulates host immune responses in a manner that promotes life with unwanted guests.
The quorum sensing volatile molecule 2-amino acetophenon modulates host immune responses in a manner that promotes life with unwanted guests.
复制标题
法定感应的挥发性分子2-氨基乙烯酮以促进不必要的客人生活的方式调节宿主免疫反应。
DOI：
10.1371/journal.ppat.1003024
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Rahme LG
中科院分区：
文献类型：
--
作者：
Bandyopadhaya A;Kesarwani M;Que YA;He J;Padfield K;Tompkins R;Rahme LG
越来越多的证据表明细菌群体感应（QS）信号是免疫调节的重要介质。然而，微生物是否利用这些免疫调节信号来维持感染仍不清楚。在这里，我们发现铜绿假单胞菌 QS 调节分子 2-氨基苯乙酮 (2-AA) 以增强宿主应对这种病原体的能力的方式调节宿主免疫反应。感染前接受 2-AA 治疗的小鼠的存活率为 90%，而未经预处理的感染小鼠的存活率为 10%。虽然 2-AA 刺激会激活涉及丝裂原激活蛋白激酶 (MAPK)、核因子 (NF)-κB 和促炎细胞因子的关键先天免疫反应途径，但它会在预处理后减弱免疫反应激活，很可能是通过上调抗炎细胞因子来实现的。 2-AA 宿主预处理的特点是 c-JUN N 末端激酶 (JNK) 和 NF-κB 激活的转录调节阻断，以及相对保留的细胞外调节激酶 (ERK) 1/2 的激活。这些激酶变化导致 CCAAT/增强子结合蛋白-β (c/EBPβ) 激活并形成 c/EBPβ-p65 复合物，从而阻止 NF-κB 激活。 2-AA 能够抑制炎症过程，同时提高宿主存活率和病原体持久性，这与它向细菌发出信号以切换到慢性感染模式的能力相一致。我们的结果揭示了 QS 免疫调节信号，可促进王国间交流的原始方面。我们认为这种交流促进病原体的持久性，同时使宿主能够耐受感染。 铜绿假单胞菌是一种顽固的革兰氏阴性机会致病菌，无法用抗生素根除，并且是当前经常引起无法治疗的急性或慢性感染的高度问题病原体的例证。越来越多的证据表明，细菌病原体分泌的小分子可能通过影响免疫等功能来影响人类健康。尽管此类有利于急性感染的小分子已有报道，但可能影响病原体免疫反应、有利于维持慢性感染的小分子尚未有报道。我们最近发表的研究表明，铜绿假单胞菌小分子 2-氨基苯乙酮 (2-AA) 促进与慢性感染相关的细菌表型和遗传变化。在这里，我们提供的证据表明，这种具有诊断意义的重要挥发性小分子可以抑制感染引发的宿主炎症过程，从而有利于慢性感染。 2-AA 通过平衡体内和体外促炎介质和抗炎介质的分泌来限制炎症反应，同时提高铜绿假单胞菌感染的存活率。 2-AA 能够抑制炎症过程，同时提高宿主存活率和病原体持久性，表明该分子可促进宿主对感染的耐受性。我们的研究结果为病原体武器和用于使细菌长期存在于受感染组织中的机制提供了新的见解。
Increasing evidence indicates that bacterial quorum sensing (QS) signals are important mediators of immunomodulation. However, whether microbes utilize these immunomodulatory signals to maintain infection remain unclear. Here, we show that the Pseudomonas aeruginosa QS-regulated molecule 2-amino acetophenone (2-AA) modulates host immune responses in a manner that increases host ability to cope with this pathogen. Mice treated with 2-AA prior to infection had a 90% survival compared to 10% survival rate observed in the non-pretreated infected mice. Whilst 2-AA stimulation activates key innate immune response pathways involving mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-κB, and pro-inflammatory cytokines, it attenuates immune response activation upon pretreatment, most likely by upregulating anti-inflammatory cytokines. 2-AA host pretreatment is characterized by a transcriptionally regulated block of c-JUN N-terminal kinase (JNK) and NF-κB activation, with relatively preserved activation of extracellular regulated kinase (ERK) 1/2. These kinase changes lead to CCAAT/enhancer-binding protein-β (c/EBPβ) activation and formation of the c/EBPβ-p65 complex that prevents NF-κB activation. 2-AA's aptitude for dampening the inflammatory processes while increasing host survival and pathogen persistence concurs with its ability to signal bacteria to switch to a chronic infection mode. Our results reveal a QS immunomodulatory signal that promotes original aspects of interkingdom communication. We propose that this communication facilitates pathogen persistence, while enabling host tolerance to infection. Pseudomonas aeruginosa, a recalcitrant Gram-negative opportunistic pathogen, defies eradication by antibiotics and exemplifies current highly problematic pathogens that often cause untreatable acute or chronic infections. There is increasing evidence that small molecules excreted by bacterial pathogens may impact human health by affecting functions including immunity. Although such small molecules in favor of acute infections have been reported, small molecules that may impact immune responses in pathogens' favor of maintaining a chronic infection have not. We recently published work showing that the P. aeruginosa small molecule 2-amino acetophenone (2-AA) promotes bacterial phenotypic and genetic changes associated with chronic infection. Here, we provide evidence that this diagnostically important small volatile molecule dampens the host inflammatory process triggered by infection, thus favoring chronic infection. 2-AA limits the inflammatory response by balancing the secretion of pro- and anti-inflammatory mediators in vivo, as well as in vitro, while improving survival against P. aeruginosa infection. The ability of 2-AA to dampen inflammatory processes, while increasing host survival and pathogen persistence, suggests that this molecule promotes host tolerance to infection. Our findings provide novel insights into pathogen weapons and mechanisms used to enable long-term bacterial presence in infected tissues.
登录
查看更多内容
影响因子：
4.4
作者：
Aneja, Rajesh;Odoms, Kelli;Wong, Hector R.
通讯作者：
Wong, Hector R.
影响因子：
2.1
作者：
Corby-Harris, V.;Habel, K. E.;Promislow, D. E. L.
通讯作者：
Promislow, D. E. L.
影响因子：
4.4
作者：
Hawiger, J
通讯作者：
Hawiger, J
影响因子：
6
作者：
Boontham, Pisake;Robins, Adrian;Eremin, Oleg
通讯作者：
Eremin, Oleg
影响因子：
9.8
作者：
Blackwell, TS;Christman, JW
通讯作者：
Christman, JW