Quinolone and acyl-homoserine lactone quorum sensing in chronic P. aeruginosa infections

项目摘要 群体感应(Qs)是许多细菌用来调节基因的一种细胞间通讯系统。 以协调的方式表达。我们的工作重点是铜绿假单胞菌的QS系统， 一种腐生的和有机会的人类病原体。铜绿假单胞菌使用QS规范数十种 基因，包括几个重要的毒力因子。铜绿假单胞菌QS是通过转录介导的 LasR和RhlR因子，它们响应酰基高丝氨酸内酯信号，以及PqsR，它响应 烷基喹诺酮信号。铜绿假单胞菌中QS的初始特征描述了一个等级：LasR 调节RhlR和PqsR的活性。在过去的几年里，我们和其他人已经证明了这一点 层级结构是可塑性的。在缺乏功能性LasR的情况下，RhlR和PqsR可以被激活 许多环境，特别是从囊性纤维症患者的慢性肺部感染中分离出来的环境 (Cf)。这些结果表明，QS基因发生了“重新连接”，这对维持菌株的毒力功能至关重要。 慢性感染。 这一建议建立在我们之前的观察基础上，以询问这种替代生物的生物学意义 慢性萎缩性胃炎患者的细菌分离层级。我们利用CF分离株和一个实验室模型 试图问：i)铜绿假单胞菌QS的结构是如何改变的？ii)在这个改变的层次结构中， RhlR和PqsR QS是否相互作用影响慢性感染分离株的毒力功能？ 高度保守、统一调节的QS非核糖体多肽合成酶的作用是什么？ 这些问题的答案将定义RhlR和PqsR在铜绿假单胞菌中的核心重要性 慢性感染，并为未来设计针对RhlR或PQS QS的治疗药物提供信息 细菌。

Project Summary Quorum sensing (QS) is a cell-cell communication system used by many bacteria to regulate gene expression in a coordinated manner. Our work focuses on the QS system of Pseudomonas aeruginosa, a saprophyte and opportunistic pathogen of humans. P. aeruginosa uses QS to regulate dozens of genes, including several important virulence factors. P. aeruginosa QS is mediated by the transcription factors LasR and RhlR, which respond to acyl-homoserine lactone signals, and PqsR, which responds to alkylquniolone signals. Initial characterizations of QS in P. aeruginosa described a hierarchy: LasR regulates RhlR and PqsR activity. Over the past several years we, and others, have shown that this hierarchy is malleable. RhlR and PqsR can be active in the absence of functional LasR in isolates from many settings, particularly those isolated from the chronic lung infections of people with cystic fibrosis (CF). These results suggest a “rewiring” of QS that is critical to the maintenance of virulence functions in chronic infections. This proposal builds on our previous observations to ask about the biological significance of this alternate hierarchy in bacterial isolates from people with CF. We make use of CF isolates and a laboratory model strain to ask i) how is the architecture of QS of P. aeruginosa altered?; ii) in this altered hierarchy, how do RhlR and PqsR QS interact to effect virulence functions in isolates from chronic infection?; and iii) what is the role of a highly-conserved, uniformly QS regulated, non-ribosomal peptide synthetase? The answers to these questions will define the central importance of RhlR and PqsR in P. aeruginosa from chronic infections and inform future efforts to design therapeutics targeting RhlR or PQS QS in this bacterium.