Bacteria detect neutrophils via a system that responds to hypochlorous acid and flow

Neutrophils kill bacteria by producing an array of lethal molecules, including hypochlorous acid (HOCl). The extent to which pathogens detect HOCl from neutrophils and defend themselves appropriately has not been understood. We report that the opportunistic pathogen Pseudomonas aeruginosa responds to activated neutrophils by upregulating its expression of an operon which was previously shown to be activated by fluid flow, and named the flow regulated operon (Fro). We found that fro is upregulated in a mouse infection model where neutrophil influx occurs, specifically by HOCl and not by other neutrophil defense factors including LL-37, histones, or H ₂ O ₂ . HOCl preferentially oxidizes methionine and cysteine residues. As the Fro operon is regulated by the anti-σ factor FroI, which contains the highest density of these residues of all anti-σ factors, this raises the possibility that FroI is an HOCl sensor. In support of this, we found that via the σ factor FroR, HOCl induces upregulation of methionine sulfoxide reductases that relieve otherwise lethal oxidative stress. These findings suggest a model in which flow transports oxidizing molecules that activate the fro operon, establishing an early warning system for P. aeruginosa that improves its survival against host immune defenses and persistence during infection.