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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.

SUBMITTER: Mould DL

PROVIDER: S-EPMC7448281 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Mould Dallas L DL Botelho Nico J NJ Hogan Deborah A DA

mBio 20200825 4

The opportunistic pathogen <i>Pseudomonas aeruginosa</i> damages hosts through the production of diverse secreted products, many of which are regulated by quorum sensing (QS). The <i>lasR</i> 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 hyperprodu ...[more]

PMID: 32843558

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Project description:With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed.

Project description:Multidrug-resistance bacteria commonly use cell-to-cell communication that leads to biofilm formation as one of the mechanisms for developing resistance. Quorum sensing inhibition (QSI) is an effective approach for the prevention of biofilm formation. A Gram-negative bacterium, Delftia tsuruhatensis SJ01, was isolated from the rhizosphere of a species of sedge (Cyperus laevigatus) grown along the coastal-saline area. The isolate SJ01 culture and bacterial crude extract showed QSI activity in the biosensor plate containing the reference strain Chromobacterium violaceum CV026. A decrease in the violacein production of approximately 98% was detected with the reference strain C. violaceum CV026. The bacterial extract (strain SJ01) exhibited anti-quorum sensing activity and inhibited the biofilm formation of clinical isolates wild-type Pseudomonas aeruginosa PAO1 and P. aeruginosa PAH. A non-toxic effect of the bacterial extract (SJ01) was detected on the cell growth of the reference strains as P. aeruginosa viable cells were present within the biofilm. It is hypothesized that the extract (SJ01) may change the topography of the biofilm and thus prevent bacterial adherence on the biofilm surface. The extract also inhibits the motility, virulence factors (pyocyanin and rhamnolipid) and activity (elastase and protease) in P. aeruginosa treated with SJ01 extract. The potential active compound present was identified as 1,2-benzenedicarboxylic acid, diisooctyl ester. Microarray and transcript expression analysis unveiled differential expression of quorum sensing regulatory genes. The key regulatory genes, LasI, LasR, RhlI, and RhlR were down-regulated in the P. aeruginosa analyzed by quantitative RT-PCR. A hypothetical model was generated of the transcriptional regulatory mechanism inferred in P. aeruginosa for quorum sensing, which will provide useful insight to develop preventive strategies against the biofilm formation. The potential active compound identified, 1,2-benzenedicarboxylic acid, diisooctyl ester, has the potential to be used as an anti-pathogenic drug for the treatment of biofilm-forming pathogenic bacteria. For that, a detailed study is needed to investigate the possible applications.

Dataset Information

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

Publications

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

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