A Signaling Network Reciprocally Regulates Genes Associated with Acute Infection and Chronic Persistence in Pseudomonas aeruginosa

Abstract

The opportunistic pathogen Pseudomonas aeruginosa causes a variety of acute and chronic infections. We identified a gene whose inactivation results in attenuation of virulence due to premature activation of genes involved in biofilm formation and coordinate repression of genes required for initial colonization. This gene, retS, encodes a hybrid sensor kinase/response regulator with an unconventional arrangement of functional domains. Genome-wide transcriptional profiling indicates that the retS gene is required for expression of the Type III secretion system and other virulence factors and for repression of genes responsible for exopolysaccharide components of the P. aeruginosa biofilm matrix. These disparate phenotypes are suppressed by transposon insertions in genes encoding the GacS/GacA/rsmZ signal transduction pathway, a highly conserved system involved in the control of diverse adaptive functions. This study defines RetS as a pleiotropic regulator of multiple virulence phenotypes that orchestrates genes required for acute infection and genes associated with chronic persistence.

Direct interaction between sensor kinase proteins mediates acute and chronic disease phenotypes in a bacterial pathogen

“…Previous genetic studies of the opportunistic pathogen P. aeruginosa implicated at least three orphan sensor kinases (GacS, RetS, and LadS) in coordinating the expression of virulence factors associated with the transition between acute and chronic infections (Goodman et al 2004;Laskowski and Kazmierczak 2006;Ventre et al 2006). A comparison of transcriptomes of wild-type P. aeruginosa with those of a retS and a retS gacS double mutant shows a significant overlap.…”

“…This explanation for RetS function, however, seems very unlikely. Genomewide transcriptional profiling indicates that gacS and gacA transcript levels are not altered in a retS mutant, suggesting that RetS does not influence the expression of either one of these genes (Goodman et al 2004). To assess whether other regulatory factors are required for RetS-mediated rsmZ regulation, we screened an ;100,000-colony transposon insertion library for mutants that induce or repress rsmZ-lacZ transcription.…”

“…The unusual hybrid sensor kinase RetS (Fig. 1A) is required for TTSS activation, concomitant repression of biofilm formation, and colonization/dissemination in murine acute infection models (Goodman et al 2004;Laskowski et al 2004;Zolfaghar et al 2005). Genes under RetS control are inversely regulated by two other sensor kinases: GacS and LadS.…”

Sticky Situations: Key Components That Control Bacterial Surface Attachment

“…RetS negatively controls rsmY and rsmZ gene expression, while LadS positively controls sRNA levels. Inactivation of retS was shown to result in hyperattachment with elevated Psl exopolysaccharide gene expression and suppression of the TTSS, with the phenotype abolished by a secondary mutation in gacS (53). In contrast, LadS inactivation was found to result in decreased attachment, reduced Psl production, and elevated TTSS expression, suggesting that LadS may function to counteract RetS.…”

“…In P. aeruginosa, RsmA function is antagonized by the sRNAs rsmZ and rsmY, whose expression is directly controlled by GacA/GacS, the TCS homolog of the E. coli BarA/UvrY system (reviewed in reference 107). GacA/GacS function is, in turn, inversely controlled by the two-component hybrids RetS and LadS (53,161). RetS negatively controls rsmY and rsmZ gene expression, while LadS positively controls sRNA levels.…”