A Unique Regulator Contributes to Quorum Sensing and Virulence in Burkholderia cenocepacia

Abstract

Burkholderia cenocepacia causes chronic and life-threatening respiratory infections in immunocompromized people. The B. cenocepacia N-acyl-homoserine lactone (AHL)-dependent quorum sensing system relies on the production of AHLs by the synthases CepI and CciI while CepR, CciR and CepR2 control expression of many genes important for pathogenesis. Downstream from, and co-transcribed with cepI, lies BCAM1871 encoding a hypothetical protein that was uncharacterized prior to this study. Orthologs of B. cenocepacia BCAM1871 are uniquely found in Burkholderia spp and are conserved in their genomic locations in pathogenic Burkholderia. We observed significant effects on AHL activity upon mutation or overexpression of BCAM1871, although these effects were more subtle than those observed for CepI indicating BCAM1871 acts as an enhancer of AHL activity. Transcription of cepI, cepR and cciIR was significantly reduced in the BCAM1871 mutant. Swimming and swarming motilities as well as transcription of fliC, encoding flagellin, were significantly reduced in the BCAM1871 mutant. Protease activity and transcription of zmpA and zmpB, encoding extracellular zinc metalloproteases, were undetectable in the BCAM1871 mutant indicating a more significant effect of mutating BCAM1871 than cepI. Exogenous addition of OHL restored cepI, cepR and fliC transcription but had no effect on motility, protease activity or zmpA or zmpB transcription suggesting AHL-independent effects. The BCAM1871 mutant exhibited significantly reduced virulence in rat chronic respiratory and nematode infection models. Gene expression and phenotypic assays as well as vertebrate and invertebrate infection models showed that BCAM1871 significantly contributes to pathogenesis in B. cenocepacia.

Is There Potential for Repurposing Statins as Novel Antimicrobials?

“…Bacterial cell-cell communication may not be impacted by statins, as simvastatin, lovastatin, and mevastatin failed to alter N-acyl-homoserine lactone (AHL) or Pseudomonas quinolone signal (PQS) quorum sensing by P. aeruginosa and mevastatin failed to alter AHL signaling by Burkholderia cenocepacia, both prominent causes of respiratory infections in cystic fibrosis patients (67,74). In the same studies, transcription of the exoS type three secretion toxin and protease production, respectively, were not altered by the statins tested.…”

Cross-Species Comparison of the Burkholderia pseudomallei, Burkholderia thailandensis, and Burkholderia mallei Quorum-Sensing Regulons

“…B. thailandensis and B. pseudomallei mutants in this ortholog (BP1026B_II0970/BTH_II1513) showed reduced survival in Dictyostelium discoideum amoeba but were able to replicate to wild type-levels during intracellular infection assays in RAW 264.7 cells (46). In Burkholderia cenocepacia, an orthologous gene acts as an enhancer of AHL-mediated phenotypes (47). The organization of the QS-1 system and the QS-enhancer genes shows a high degree of synteny among B. cenocepacia and the Bptm group, raising the possibility that this gene has a broad role in the QS-controlled phenotypes of related Burkholderia.…”

The Organization of the Quorum Sensing luxI/R Family Genes in Burkholderia

“…cciI and cciR are transcribed in the same direction and accordingly the topology is named as R1. All B. cenocepacia members contain a solo or orphan luxR homolog named as cepR2 [29,56]. All QS systems are present on chromosome 2 except in some cases— bviI/R of B. vietnamiensis (X5 topology) and luxI/rsaM of B. ambifaria .…”