Quorum sensing controls the Pseudomonas aeruginosa CRISPR Cas adaptive immune system
Significance The cell cell communication process, called quorum sensing, activates all three key aspects of the prokaryotic adaptive immune system (termed CRISPR Cas) expression, activity, and adaptation in the pathogen Pseudomonas aeruginosa. We show that pro and antiquorum sensing compounds activate and repress CRISPR Cas, respectively, suggesting the exciting possibility of a combination quorum sensing inhibition phage therapy cocktail. In P. aeruginosa, quorum sensing inhibitors repress virulence, making P. aeruginosa more susceptible to elimination by the human immune system, while simultaneously making P. aeruginosa more prone to killing by phage therapy through inhibition of the CRISPR Cas defense mechanism. Finally, because we show that quorum sensing activates adaptation by the CRISPR Cas immune system, a quorum sensing inhibitor should also reduce acquisition of resistance against the administered phage. CRISPR Cas are prokaryotic adaptive immune systems that provide protection against bacteriophage (phage) and other parasites. Little is known about how CRISPR Cas systems are regulated, preventing prediction of phage dynamics in nature and manipulation of phage resistance in clinical settings. Here, we show that the bacterium Pseudomonas aeruginosa PA14 uses the cell cell communication process, called quorum sensing, to activate cas gene expression, to increase CRISPR Cas targeting of foreign DNA, and to promote CRISPR adaptation, all at high cell density. This regulatory mechanism ensures maximum CRISPR Cas function when bacterial populations are at highest risk for phage infection. We demonstrate that CRISPR Cas activity and acquisition of resistance can be modulated by administration of pro and antiquorum sensing compounds. We propose that quorum sensing inhibitors could be used to suppress the CRISPR Cas adaptive immune system to enhance medical applications, including phage therapies.
Proceedings of the National Academy of Sciences