Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS Pathog. 2011 Aug;7(8):e1002192. doi: 10.1371/journal.ppat.1002192. Epub 2011 Aug 4.
A significant number of environmental microorganisms can cause serious, even fatal, acute and chronic infections in humans. The severity and outcome of each type of infection depends on the expression of specific bacterial phenotypes controlled by complex regulatory networks that sense and respond to the host environment. Although bacterial signals that contribute to a successful acute infection have been identified in a number of pathogens, the signals that mediate the onset and establishment of chronic infections have yet to be discovered. We identified a volatile, low molecular weight molecule, 2-amino acetophenone (2-AA), produced by the opportunistic human pathogen Pseudomonas aeruginosa that reduces bacterial virulence in vivo in flies and in an acute mouse infection model. 2-AA modulates the activity of the virulence regulator MvfR (multiple virulence factor regulator) via a negative feedback loop and it promotes the emergence of P. aeruginosa phenotypes that likely promote chronic lung infections, including accumulation of lasR mutants, long-term survival at stationary phase, and persistence in a Drosophila infection model. We report for the first time the existence of a quorum sensing (QS) regulated volatile molecule that induces bistability phenotype by stochastically silencing acute virulence functions in P. aeruginosa. We propose that 2-AA mediates changes in a subpopulation of cells that facilitate the exploitation of dynamic host environments and promote gene expression changes that favor chronic infections.
相当数量的环境微生物可以在人类中引起严重的、甚至致命的急性和慢性感染。每种类型感染的严重程度和结果取决于特定细菌表型的表达，这些表型受感知和响应宿主环境的复杂调控网络控制。虽然已经在一些病原体中鉴定出有助于成功急性感染的细菌信号，但介导慢性感染发生和建立的信号尚未被发现。我们鉴定出一种挥发性、低分子量分子 2-氨基苯乙酮（2-AA），它由机会性病原体铜绿假单胞菌产生，可降低苍蝇体内和急性小鼠感染模型中细菌的毒力。2-AA 通过负反馈回路调节毒力调节因子 MvfR（多种毒力因子调节因子）的活性，并促进铜绿假单胞菌表型的出现，这些表型可能促进慢性肺部感染，包括 lasR 突变体的积累、在静止期的长期存活以及在果蝇感染模型中的持续存在。我们首次报告了一种群体感应（QS）调节的挥发性分子的存在，该分子通过随机沉默铜绿假单胞菌中的急性毒力功能诱导双稳态表型。我们提出 2-AA 介导了细胞亚群的变化，这些变化有利于利用动态宿主环境，并促进有利于慢性感染的基因表达变化。
