Analysis of Pseudomonas aeruginosa Diguanylate Cyclases and Phosphodiesterases Reveals a Role for Bis-(3'-5')-Cyclic-GMP in Virulence

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作者：

Kulesekara, H，Lee, V，Brencic, A，Liberati, N，Urbach, J，Miyata, S，Lee, DG，Neely, AN，Hyodo, M，Hayakawa, Y

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摘要：

The opportunistic pathogen 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 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鈥5鈥-cyclic dimeric GMP (c-di-GMP) was identified in the annotated genomes of strains PAO1 and PA14. Although the majority of these genes are components of the core genome, several are located on presumptive horizontally acquired genomic islands. A comprehensive analysis of 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.

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关键词：

cytotoxicity biofilm CYCLIC DI-GMP BIOFILM FORMATION VIBRIO-CHOLERAE SIGNAL-TRANSDUCTION CELLULOSE BIOSYNTHESIS ACETOBACTER-XYLINUM III SECRETION EAL DOMAINS SYSTEM BACTERIA