The Mucoid Switch in <i>Pseudomonas aeruginosa</i> Represses Quorum Sensing Systems and Leads to Complex Changes to Stationary Phase Virulence Factor Regulation

<div><p>The opportunistic pathogen <i>Pseudomonas aeruginosa</i> chronically infects the airways of Cystic Fibrosis (CF) patients during which it adapts and undergoes clonal expansion within the lung. It commonly acquires inactivating mutations of the anti-sigma factor MucA leading to a mucoid phenotype, caused by excessive production of the extracellular polysaccharide alginate that is associated with a decline in lung function. Alginate production is believed to be the key benefit of <i>mucA</i> mutations to the bacterium in the CF lung. A phenotypic and gene expression characterisation of the stationary phase physiology of <i>mucA22</i> mutants demonstrated complex and subtle changes in virulence factor production, including cyanide and pyocyanin, that results in their down-regulation upon entry into stationary phase but, (and in contrast to wildtype strains) continued production in prolonged stationary phase. These findings may have consequences for chronic infection if mucoid <i>P. aeruginosa</i> were to continue to make virulence factors under non-growing conditions during infection. These changes resulted in part from a severe down-regulation of both AHL-and AQ (PQS)-dependent quorum sensing systems. <i>In trans</i> expression of the cAMP-dependent transcription factor Vfr restored both quorum sensing defects and virulence factor production in early stationary phase. Our findings have implications for understanding the evolution of <i>P. aeruginosa</i> during CF lung infection and it demonstrates that <i>mucA22</i> mutation provides a second mechanism, in addition to the commonly occurring <i>lasR</i> mutations, of down-regulating quorum sensing during chronic infection this may provide a selection pressure for the mucoid switch in the CF lung.</p>