Relationship of the transcription factor MexT to quorum sensing and virulence in Pseudomonas aeruginosa

Abstract

ABSTRACT Quorum sensing (QS) regulates expression of many virulence genes in the opportunistic human pathogen Pseudomonas aeruginosa . There are two acyl-homoserine lactone (AHL) QS circuits, LasI-R and RhlI-R, which together activate expression of hundreds of genes in a cell density-dependent manner. There is also an inter-related non-AHL QS circuit, the Pseudomonas Quinolone Signal (PQS) circuit. Studies of the model strain PAO1 show that AHL QS is hierarchical, with the LasI-R system required for full activity of RhlI-R. We show that the LysR-type transcription factor MexT is an important modulator of the RhlI-R and PQS circuits. MexT delays the expression of genes activated by PQS and by the RhlI-R circuits but not genes regulated by the LasI-R circuit. In PAO1, MexT is constitutively active because of a mutation in mexS , a gene involved in maintaining redox homeostasis. Consistent with other reports, we show that in another model strain, PA14, MexT is quiescent but is activated by disulfide stress, and we show that this is true for all clinical isolates we tested. Compared with strain PA14, strain PAO1 has a virulence defect in a Caenorhabditis elegans infection model. We show that PAO1 mutants with inactive MexT are more virulent than their parent during C. elegans infection. Conversely, a PA14 mutant with a constitutively active MexT is attenuated for virulence. Our findings point to an important role for MexT as a governor of P. aeruginosa virulence and show that MexT limits virulence though its inhibition of the RhlI-R system. IMPORTANCE Pseudomonas aeruginosa is an opportunistic bacterial pathogen. Many of its virulence genes are regulated by quorum sensing (QS), a form of cell-to-cell communication. P. aeruginosa QS consists of three interlinked circuits, LasI-R, Rhl-R, and Pseudomonas quinolone signal (PQS). Additionally, its QS system is interconnected with other regulatory networks, which help optimize gene expression under variable conditions. The numbers of genes regulated by QS differ substantially among P. aeruginosa strains. We show that a regulatory factor MexT, which is activated in response to certain antibiotics, downregulates the RhlI-R circuit and in turn measurably lowers virulence in a nematode worm infection model. Our findings help understand how existing and future therapeutic interventions for P. aeruginosa infections may impact this bacterium’s gene regulation and physiology.