Author:
Almblad Henrik,Harrison Joe J.,Rybtke Morten,Groizeleau Julie,Givskov Michael,Parsek Matthew R.,Tolker-Nielsen Tim
Abstract
ABSTRACTThe opportunistic human pathogenPseudomonas aeruginosaexpresses 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-typeP. aeruginosabiofilms have high c-di-GMP levels and low cAMP levels.IMPORTANCEOur work suggests that cross talk between c-di-GMP and cAMP signaling pathways results in downregulation of acute virulence factors inP. aeruginosabiofilm infections. Knowledge about this cross-regulation adds to our understanding of virulence traits and immune evasion byP. aeruginosain chronic infections and may provide new approaches to eradicate biofilm infections.
Publisher
American Society for Microbiology
Subject
Molecular Biology,Microbiology
Cited by
67 articles.
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