Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3′-5′)-cyclic-GMP in virulence
Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3′-5′)-cyclic-GMP in virulence
复制标题
DOI：
10.1073/pnas.0511090103
复制
发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Lory, S
中科院分区：
文献类型：
--
作者：
Kulesekara, H;Lee, V;Lory, S
条件致病菌铜绿假单胞菌是导致免疫功能低下个体全身感染和囊性纤维化患者慢性呼吸道疾病的原因。已知环核苷酸在致病菌中的毒力相关因子的调节中发挥多种作用。在铜绿假单胞菌菌株PAO 1和PA 14的注释基因组中鉴定了一组铜绿假单胞菌基因，其编码含有二鸟苷酸环化酶（DGC）和磷酸二酯酶（PDE）的推定结构域特征的蛋白质，所述结构域负责维持第二信使双-（3 '-5'）-环状二聚GMP（c-di-GMP）的细胞水平。虽然这些基因中的大多数是铜绿假单胞菌核心基因组的组成部分，有几个位于假定的水平获得的基因组岛。对编码c-di-GMP代谢酶的铜绿假单胞菌基因（DGC-和PDE-编码基因）进行全面分析，以分析c-di-GMP在两种疾病相关现象（细胞毒性和生物膜形成）中的功能。DGC和PDE突变体和过表达克隆的表型分析显示，某些毒力相关性状通过改变c-di-GMP水平由多种DGC和PDE控制。一组选定的DGC和PDE编码基因的突变体在小鼠感染模型中表现出减弱的毒力。考虑到不同DGC和PDE基因中的插入导致不同的表型，这些酶对c-di-GMP的形成或降解似乎是高度定位的，并与c-di-GMP作用的特定靶点密切相关。
The opportunistic pathogen Pseudomonas aeruginosa is responsible for systemic infections in immunocompromised individuals and chronic respiratory disease in patients with cystic fibrosis. Cyclic nucleotides are known to play a variety of roles in the regulation of virulence-related factors in pathogenic bacteria. A set of P. aeruginosa genes, encoding proteins that contain putative domains characteristic of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) that are responsible for the maintenance of cellular levels of the second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) was identified in the annotated genomes of P. aeruginosa strains PAO1 and PA14. Although the majority of these genes are components of the A aeruginosa core genome, several are located on presumptive horizontally acquired genomic islands. A comprehensive analysis of P. aeruginosa genes encoding the enzymes of c-di-GMP metabolism (DGC- and PDE-encoding genes) was carried out to analyze the function of c-di-GMP in two disease-related phenomena, cytotoxicity and biofilm formation. Analysis of the phenotypes of DGC and PDE mutants and overexpressing clones revealed that certain virulence-associated traits are controlled by multiple DGCs and PDEs through alterations in c-di-GMP levels. A set of mutants in selected DGC- and PDE-encoding genes exhibited attenuated virulence in a mouse infection model. Given that insertions in different DGC and PDE genes result in distinct phenotypes, it seems likely that the formation or degradation of c-di-GMP by these enzymes is in highly localized and intimately linked to particular targets of c-di-GMP action.