The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa

Abstract

SUMMARY Cell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacterium Pseudomonas aeruginosa . All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e., N -acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production.

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

“…Among these, proteases can disrupt lung tissue and modulate host inflammatory response [6–8]; the blue-green pigment pyocyanin causes host cells oxidative stress and dysregulates immune mechanisms [9–11]; the siderophore pyoverdine is both able to sequester iron from host depots and to regulate bacterial virulence [12,13]. In a previous study, we observed that macrolide antibiotic azithromycin (AZM) acts on P. aeruginosa by reducing the synthesis of proteases and other exoproducts involved in bacterial virulence and the associated host inflammatory response.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Exceptions to this are species that utilize multiple synthase/receptor pairs that generate and respond to distinct AHL molecules, as is the case for P. aeruginosa (Fig. 1B) (7), as well as species that carry so-called "solo" LuxR-type receptors that have no cognate LuxI-type synthase, such as QscR of P. aeruginosa and SidA of Escherichia coli (33). …”

“…Second, quorum sensing regulates the expression of numerous virulence-related products and has been shown to be important for P. aeruginosa pathogenesis in various model infection systems. Third, this pathogen poses a large burden on the medical community due to its extensive resistance to antibiotics and the current lack of effective treatment options (7), and thus discovery of quorumquenching inhibitors amenable to therapeutic applications would be of high value. Quorum sensing in P. aeruginosa is a complex network comprised of at least three distinct signal/receptor pairs that function in a hierarchical fashion (Fig.…”

“…Each QS system also regulates various virulence factor-encoding genes, some of which are coregulated by the other QS systems. Additionally, there is also a solo LurR-type protein, QscR, that binds 3OC12HSL and subsequently inhibits both the las and rhl QS systems by multiple mechanisms (6,7).…”

“…Although only P. aeruginosa produces PQS, other species of Pseudomonas as well as Burkholderia spp. utilize HHQ as a quorum-sensing signal (6,7).…”