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.
Highlights
The opportunistic pathogen Pseudomonas aeruginosa damages hosts through the production of diverse secreted products, many of which are regulated by quorum sensing (QS)
The higher levels of pyocyanin in wild type (WT)/ΔlasR cocultures relative to levels in single-strain cultures were observed on artificial sputum medium (ASM) and on phosphate-buffered medium with or without amino acids, indicating that the phenomenon occurred under diverse conditions
We found that WT/ΔlasR cocultures had fewer CFU than WT monocultures on lysogeny broth (LB) medium (Fig. S1D)
Summary
The opportunistic pathogen Pseudomonas aeruginosa damages hosts through the production of diverse secreted products, many of which are regulated by quorum sensing (QS). A metabolite often secreted in low iron environments, stimulated RhlR signaling and RhlI levels in LasRϪbut not in LasRϩ strains These studies reveal the potential for complex interactions between recently diverged, genetically distinct isolates within populations from single chronic infections. ® mbio.asm.org 1 regulatory networks described in widely used P. aeruginosa model strains, LasR is an upstream regulator of RhlR and PqsR signaling, and together these regulators control the expression of a suite of genes associated with virulence, including redox-active small-molecule phenazines [18,19,20], cyanide [21], and rhamnolipid surfactants important for surface motility, biofilm dispersal, and host cell damage [22,23,24]. LasRϪ strains can activate QS in response to specific fungal products [29] or culture conditions [30, 31]
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