Mucin glycans signal through the sensor kinase RetS to inhibit virulence-associated traits in Pseudomonas aeruginosa

Mucus is a densely populated ecological niche that coats all epithelia, and plays a critical role in protecting the human body from infections. Although traditionally viewed as a physical barrier, emerging evidence suggests that mucus can directly suppress virulence traits in opportunistic pathogens like Pseudomonas aeruginosa. However, the molecular mechanisms by which mucus affords this protection are unclear. Here, we show that mucins, and particularly their associated glycans, activate the sensor kinase RetS via its Dismed2 domain in P. aeruginosa. We find that this RetS-dependent signaling leads to the direct inhibition of the GacS-GacA two-component system, the activity of which is associated with a chronic infection state. This signaling includes the downregulation of the type VI secretion system (T6SS), and prevents T6SS-dependent bacterial killing by P. aeruginosa. Overall, these results shed light on how mucus impacts P. aeruginosa behavior in the human host, and may inspire novel approaches for controlling P. aeruginosa infections.