# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Virulence Factors
#### 4.1.4 Multiple Signalling Systems in the Regulation of Virulence Genes  
Quorum Sensing System  
Bacterial communication is the term given to the regulation of bacterial behavior in response to the presence of other cells. Cell-to-cell communication is based on the generation and release of small signaling molecules. These small signaling molecules, called autoinducers, are involved in a form of regulation known as quorum sensing (QS) [117]. QS is often referred to as \"density-dependent\" because a critical density of bacterial cells is necessary for the level of autoinducer to reach the limit, stimulus concentration and bind to the activator protein, causing expression of the target gene [118]. QS signaling molecules also regulate the expression of various virulence factors, adhesion, and motility, and control biofilm formation by _P. aeruginosa_[119]. Three distinct quorum sensing systems have been described in _P. aeruginosa_: two LuxIR homologs (_las_ and _rhl_), involving two N-acyl homoserine lactone (AHLs) dependent systems, and the 2-heptyl-3-hydroxy-4-(1H)-quinolone (PQS) [120,121]. The _las_ system is composed of LasI, a synthase protein, which produces the autoinducer N-3-oxo-dodecanoyl homoserine lactone (3 OC12 HSL), that binds to the transcriptional activator protein (LasR) at a threshold concentration. The 3 OC12 HSL-LasR complex binds to promoter regions upstream of genes that encode for a range of virulence factors (such as elastase, exotoxin A, and alkaline protease). The _las_ system positively regulates the _rhl_ and _pqs_ systems. On the other hand, the _rhl_ system negatively regulates the _pqs_ system. The _pqs_ system can autoinducer PQS synthesis and activates over-expression of the _rhl_ system [3]. When the induction of the _rhl_ transcriptional activator protein, RhIR, binding with N-butyryl homoserine lactone, (C4 HSL) occurs, it leads to the synthesis of the autoinducer synthase protein (RhII) [122]. The Rh1R-C4 HSL complex can also induce the expression of several genes encoding virulence factors (such as alkaline protease, elastase, rhamnpid, pyocyanin, and HCN) and can activate genes under the control of LasR [123]. The _las_ and _rhl_ systems do not act independently of each other: rather, they are organized in an established hierarchy with a signaling cascade [124]. The third _P. aeruginosa_ QS system, PQS, is synthesized via condensation of anthranilate and \(\beta\)-keto dodecanoate [125]. The _pqsABCD_ operon encoded 2-heptyl-4(1H)-quinolone, PQS precursor, is converted to PQS by PqsH, a putative monooxygenase [117,126]. The LysR-type regulator PqsR (also known as MvfR) regulates the PQS. This system controls the biosynthesis of AHL-associated virulence factors like pyocyanin and rhamnids. It also affects biofilm development [127]. Thus, the PQS pathway is linked to the LasI/LasR and RhII/RhIR QS systems, influencing the production of virulence factors. The PQS HHQ precursor also acts as a cell-to-cell signal. HHQ can be released into the extracellular medium and then be absorbed by neighbouring cells, where it can be converted to PQS by PqsH, or bind directly to PqsR, in both cases activating PQS-regulated gene expression to levels similar to those observed in response to PQS itself [107]. Specific environmental conditions and host immune factors were associated with changes in the QS response of _P. aeruginosa_. For example, under anaerobic conditions, QS systems and transcriptional regulators (such as ANR) allow for bacterial growth and expression of virulence [128]. It should be noted that, besides the existence of the QS-systems, _P. aeruginosa_ also has two-component regulatory systems that control both its virulence phenotype and its response to environmental stimuli. Basically, the two-component regulatory systems are formed by two proteins: a histidine kinase (HK) and a response regulator (RR). One of the most important of such systems is GaCS/GaCA, which plays a critical role in controlling _P.