The transcriptional regulators of virulence for Pseudomonas aeruginosa: Therapeutic opportunity and preventive potential of its clinical infections

Abstract

In Pseudomonas aeruginosa (P. aeruginosa), transcription factors (TFs) are important mediators in the genetic regulation of adaptability and pathogenicity to respond to multiple environmental stresses and host defences. The P. aeruginosa genome harbours 371 putative TFs; of these, about 70 have been shown to regulate virulence-associated phenotypes by binding to the promoters of their target genes. Over the past three decades, several techniques have been applied to identify TF binding sites on the P. aeruginosa genome, and an atlas of TF binding patterns has been mapped. The virulence-associated regulons of TFs show complex crosstalk in P. aeruginosa's regulatory network. In this review, we summarise the recent literature on TF regulatory networks involved in the quorum-sensing system, biofilm formation, pyocyanin synthesis, motility, the type III secretion system, the type VI secretion system, and oxidative stress responses. We discuss future perspectives that could provide insights and targets for preventing clinical infections caused by P. aeruginosa based on the global regulatory network of transcriptional regulators.

Keywords: Crosstalk; Pseudomonas aeruginosa; Regulatory network; Transcriptional regulators; Virulence.

Figure 1

The QS pathway regulatory network of P. aeruginosa. The QS consists of four systems, the Las system, Rhl system, Pqs system and Iqs system, which are regulated by more than 28 transcriptional regulators with daedal networks. This regulatory network indicates the binding target genes and the crosstalk among these regulators.

Figure 2

The pyocyanin synthesis pathway regulatory network of P. aeruginosa. (Left panel) The pyocyanin synthesis regulatory network is mediated by 19 regulators (PhoB, PA3249, PA1315, PA0784, GacA, CarR, PqsE, AmrZ, QscR, QteE, RhlR, RsaL, LasR, BfmR, CzcR, RpoS, PrtR, AlgR and RsmA/N) and three co-target genes (amrZ, phzA1-G1 and phzA2-G2). (Right panel) The biosynthesis pathway of phenazines (including pyocyanin, 1-hydroxyphenazine and phenazine-1-carboxylic acid).

Figure 3

The motility regulatory network of P. aeruginosa. P. aeruginosa motility includes swarming, swimming and twitching. Swarming motility is driven by flagella, which are controlled by FleQ, two sigma factors (FliA and RpoN), two anti-sigma factors (FleN and FlgM), PA3594, and the Gac/Rsm signaling system. Swimming and twitching motility are driven by the type VI pili, which is regulated by PilRS, AlgRZ, RpoN and the Chp system. RocA1/RocR and PprB regulate the fimbriae, which are required for adherence. The motility network is mediated by 16 direct transcription regulators (such as FleQ, RpoN and PilR) and shares three co-target genes (rsmY/Z, flhA and tar-cheZ).

Figure 4

The biofilm formation pathway regulatory network of P. aeruginosa. The P. aeruginosa biofilm matrix mainly consists of three kinds of extracellular polysaccharides (Pel, Psl and alginate extracellular polysaccharide), which are synthesised by the pelA-G operon, pslA-O operon and algD-L operon, and is regulated by 29 direct transcription regulators. We have summarised the direct regulators involved in biofilm formation and re-mapped the regulatory network underlying these regulators. The network shows 10 co-target genes: amrZ, cupD, pelA-G, fleQ, pslA-O, algU, algR, algA, algD-L and algC.

Figure 5

The T3SS pathway regulatory network of P. aeruginosa. The T3SS in P. aeruginosa is regulated by two main regulatory signalling systems, Gac/Rsm-ExsA-T3SS and cAMP/Vfr-ExsA-T3SS. ExsA is the master regulator of the T3SS. The expression of ExsA is inhibited by PtrA, ExsD, MvaT/U and HigA at the transcriptional level and by Hfq, CspC and RplI at the post-transcriptional level. ExsA acts as a co-target that can be directly activated by five regulators, VqsM, Fis, Vfr, RocA1 and PsrA. The downstream T3SS effectors (such as exoS, exoT and exoY) are also directly regulated by ExsA, PA2572/PA2573, CbrAB and RocS1/A1. The T3SS is directly mediated by 21 direct regulators and six co-target genes (rsmY/Z, exsA, higB-A, exoS, exoT and exoY).

Figure 6

The T6SS pathway regulatory network of P. aeruginosa. The T6SS signalling system is mainly controlled by Gac/Rsm-H1-T6SS and AmrZ-FleQ-H1-T6SS, and is responsible for providing competitive advantages in environments with diverse bacteria. RpoN directly binds to the promoter of two effector genes (hcpA and hcpB). H2-T6SS is directly regulated by LasR and OxyR. Effector HcpC can be secreted in host cells to cause chronic infection. The T6SS network is mediated by 18 regulators and four co-target genes (rsmY/Z, tssA1-C1, amrZ and hisA2-F2).

Figure 7

The oxidative stress response regulatory network of P. aeruginosa. Five TFs (LasR, SoxR, MexR, OxyR and OspR) involved in the QS, antibiotic resistance and motility sense ROS and translocate the signals to the downstream virulence-related phenotypes. Three metabolic proteins (ExaC, ArcA and GapA) also sense and respond to ROS from the host immune system.