Intraspecies Signaling between Common Variants of Pseudomonas aeruginosa Increases Production of Quorum-Sensing-Controlled Virulence Factors

Abstract

The opportunistic pathogen Pseudomonas aeruginosa damages hosts through the production of diverse secreted products, many of which are regulated by quorum sensing (QS). The lasR gene, which encodes a central QS regulator, is frequently mutated in clinical isolates from chronic infections, and loss of LasR function (LasR−) generally impairs the activity of downstream QS regulators RhlR and PqsR. We found that in cocultures containing LasR+ and LasR− strains, LasR− strains hyperproduce the RhlR/RhlI-regulated antagonistic factors pyocyanin and rhamnolipids in diverse models and media and in different strain backgrounds. Diffusible QS autoinducers produced by the wild type were not required for this effect. Using transcriptomics, genetics, and biochemical approaches, we uncovered a reciprocal interaction between wild-type and lasR mutant pairs wherein the iron-scavenging siderophore pyochelin produced by the lasR mutant induced citrate release and cross-feeding from the wild type. Citrate, a metabolite often secreted in low iron environments, stimulated RhlR signaling and RhlI levels in LasR−but not in LasR+ strains. These studies reveal the potential for complex interactions between recently diverged, genetically distinct isolates within populations from single chronic infections. IMPORTANCE Coculture interactions between lasR loss-of-function and LasR+ Pseudomonas aeruginosa strains may explain the worse outcomes associated with the presence of LasR− strains. More broadly, this report illustrates how interactions within a genotypically diverse population, similar to those that frequently develop in natural settings, can promote unpredictably high virulence factor production.

Systematic identification of molecular mediators underlying sensing ofStaphylococcus aureusbyPseudomonas aeruginosa

“…Extracellular citrate has been detected in S. aureus cultures previously (90,91), and our work shows that this staphylococcal secreted metabolite can be sensed by P. aeruginosa, thus defining another cooperative interaction between these two coinfecting pathogens. Higher concentrations of citrate affect quorum sensing and biofilm formation, and mediate iron uptake in P. aeruginosa (60,92,93). While citrate did not affect iron pathways in our study at the concentration found in S. aureus JE2 supernatant (Table S13), it is possible that higher concentrations that facilitate iron uptake may exist in communities with these two species.…”

The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection

“…Another study on the evolution of P. aeruginosa in Caenorhabditis elegans also identified that virulence evolution was mediated by the production of secreted molecules and that attenuation in pathogenicity could be attributed to cheats exploiting the goods produced by cooperators [76]. Taken together, this highlights the importance of social interactions during chronic infection, and that heterogeneous populations likely result in complex interactions that can impact overall community function [77,84]. Future work in this area could focus on exploring genetic diversity in infections using deep sequencing, which may provide insights as to how allelic polymorphism and genetic heterogeneity impacts community function and the outcome of virulence [77].…”

Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum

“…While LasR-strains are common in CF infections, virulence factors regulated by LasR such as zinc metalloproteases are still reported to be abundant in CF sputum (57). Recent work by Mould et al showed that when LasR+ and LasR-strains were cocultured, the LasR+ strain increased production of RhlR-controlled virulence factors by the LasR-strain (69). Interestingly, LasB and LasA are reportedly regulated by both the LasR and RhlR QS regulators (35).…”