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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·2015·Journal of Bacteriology
DOI 10.1128/jb.00193-15
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Abstract

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.

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Metadata

Authors
Almblad, H., Harrison, J. J., Rybtke, M., Groizeleau, J., Givskov, M., Parsek, M. R., & Tolker-Nielsen, T.
Venue
Journal of Bacteriology
Publisher
American Society for Microbiology
Published
2015-04-20
Volume
197
Issue
13
Pages
2190-2200
ISSN
  • 0021-9193
  • 1098-5530
DOI
10.1128/jb.00193-15
Cited by
91
References
3
Language
en
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correction (2016-07-17)

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CoChat. (2026). Citation check: The cyclic AMP–Vfr signaling pathway in Pseudomonas aeruginosa is inhibited by cyclic di-GMP. https://app.cochat.ai/papers/10.1128/jb.00193-15
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Almblad, H., Harrison, J. J., Rybtke, M., Groizeleau, J., Givskov, M., Parsek, M. R., & Tolker-Nielsen, T. (2015). The cyclic AMP–Vfr signaling pathway in Pseudomonas aeruginosa is inhibited by cyclic di-GMP. Journal of Bacteriology. https://doi.org/10.1128/jb.00193-15

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