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The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP.
Almblad, Henrik; Harrison, Joe J; Rybtke, Morten; Groizeleau, Julie; Givskov, Michael; Parsek, Matthew R; Tolker-Nielsen, Tim.
Afiliação
  • Almblad H; Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Harrison JJ; Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
  • Rybtke M; Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Groizeleau J; Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Givskov M; Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
  • Parsek MR; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Tolker-Nielsen T; Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark ttn@sund.ku.dk.
J Bacteriol ; 197(13): 2190-200, 2015 Jul.
Article em En | MEDLINE | ID: mdl-25897033
UNLABELLED: The opportunistic human pathogen Pseudomonas aeruginosa expresses numerous acute virulence factors in the initial phase of infection, and during long-term colonization it undergoes adaptations that optimize survival in the human host. Adaptive changes that often occur during chronic infection give rise to rugose small colony variants (RSCVs), which are hyper-biofilm-forming mutants that commonly possess mutations that increase production of the biofilm-promoting secondary messenger cyclic di-GMP (c-di-GMP). We show that RSCVs display a decreased production of acute virulence factors as a direct result of elevated c-di-GMP content. Overproduction of c-di-GMP causes a decrease in the transcription of virulence factor genes that are regulated by the global virulence regulator Vfr. The low level of Vfr-dependent transcription is caused by a low level of its coactivator, cyclic AMP (cAMP), which is decreased in response to a high level of c-di-GMP. Mutations that cause reversion of the RSCV phenotype concomitantly reactivate Vfr-cAMP signaling. Attempts to uncover the mechanism underlying the observed c-di-GMP-mediated lowering of cAMP content provided evidence that it is not caused by inhibition of adenylate cyclase production or activity and that it is not caused by activation of cAMP phosphodiesterase activity. In addition to the studies of the RSCVs, we present evidence that the deeper layers of wild-type P. aeruginosa biofilms have high c-di-GMP levels and low cAMP levels. IMPORTANCE: Our work suggests that cross talk between c-di-GMP and cAMP signaling pathways results in downregulation of acute virulence factors in P. aeruginosa biofilm infections. Knowledge about this cross-regulation adds to our understanding of virulence traits and immune evasion by P. aeruginosa in chronic infections and may provide new approaches to eradicate biofilm infections.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Proteínas de Bactérias / Transdução de Sinais / AMP Cíclico / GMP Cíclico / Proteína Receptora de AMP Cíclico Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Proteínas de Bactérias / Transdução de Sinais / AMP Cíclico / GMP Cíclico / Proteína Receptora de AMP Cíclico Idioma: En Ano de publicação: 2015 Tipo de documento: Article