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Non-hierarchical, RhlR-regulated acyl-homoserine lactone quorum sensing in a cystic fibrosis isolate of Pseudomonas aeruginosa

Publication

Date: 2nd September 2019 | Source: BioRxiv

Authors: Renae L Cruz, Kyle L Asfahl, Sara Van den Bossche, Tom Coenye, Aurélie Crabbe, Ajai A Dandekar.

The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy, and activates the transcription of dozens of genes, including that encoding the QS regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have recently shown that in CF isolates, the QS circuitry is often “rewired” such that RhlR acts in a LasR-independent manner. To begin understanding how QS activity differs in this “rewired” background, we characterized QS activation and RhlR-regulated gene expression in P. aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR include several that encode virulence factors. Some, but not all, of these genes are present in the QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 produces virulence factors at similar concentrations to that of PAO1. Unlike PAO1, cytotoxicity by E90 in a three-dimensional lung epithelium cell model is also RhlR-regulated. These data illuminate a “rewired” LasR-independent RhlR regulon in chronic infection isolates and suggest that RhlR may be a target for therapeutic development in chronic infections.

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