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Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing
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Journal Article
Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing
2021
Overview
Pseudomonas aeruginosa
uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in
P. aeruginosa
is complex, intricate and is dominated by two main
N
-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in
P. aeruginosa
. Paradoxically, LasR mutants are frequently isolated from chronic
P. aeruginosa
infections, typically among cystic fibrosis (CF) patients. This suggests
P. aeruginosa
can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of
P. aeruginosa
from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the
rhlR
locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease
lasA
and rhamnolipid
rhlA, rhlB, rhlC.
Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e.,
mexT, mucA, algR, rpoN, exsS, ampR
). Whole genome comparisons show that
P. aeruginosa
strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI’s) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of
rhlR
has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of
lasR
. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of
rhlR
and mutation of
rhlI.
This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of
P. aeruginosa
in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
