# The Oxylipin Dependent Quorum Sensing System enhances Pseudomonas aeruginosa dissemination during burn-associated infection

## TL;DR

Burn injuries release a fatty acid that Pseudomonas aeruginosa uses to boost its virulence, and blocking this process can prevent deadly infections.

## Contribution

The discovery that P. aeruginosa uses host-derived oleic acid to activate the ODS system and enhance virulence in burn wounds.

## Key findings

- Burn injuries increase free oleic acid levels, which P. aeruginosa converts into oxylipin autoinducers to activate the ODS regulon.
- ODS-deficient mutants show reduced skin colonization and dissemination, confirming ODS's role in hypervirulence.
- Inhibiting OdsA with AB012 or immunization with recombinant OdsA improves survival and reduces bacterial spread in burned mice.

## Abstract

Pseudomonas aeruginosa is a leading cause of life-threatening infections in burn patients, yet the molecular cues driving its hypervirulence remain poorly understood. Here, we identify the Oxylipin Dependent Quorum Sensing (ODS) system as a key regulator of P. aeruginosa pathogenicity in the burn wound environment. Using a murine burn model, we show that thermal injury significantly increases free oleic acid levels in skin, which P. aeruginosa converts into oxylipin autoinducers (10-HOME and 7,10-DiHOME) via OdsA and OdsB. These molecules activate the ODS regulon, promoting bacterial invasion of burned tissue and dissemination to internal organs. ODS-deficient mutants exhibited markedly reduced skin colonization, impaired translocation across endothelial barriers, and attenuated mortality compared to wild-type strains, confirming the role of ODS in hypervirulence. Importantly, immunization with recombinant OdsA or treatment with a small-molecule OdsA inhibitor significantly improved survival and reduced bacterial dissemination in burned mice. High-throughput screening identified AB012 as a potent OdsA inhibitor, which competitively binds the enzyme’s catalytic site and suppresses oxylipin synthesis, ODS gene expression, and biofilm formation without affecting bacterial growth. In vivo, AB012 reduced bacterial burden and systemic spread following burn injury. Collectively, these findings reveal that P. aeruginosa exploits host-derived oleic acid to activate ODS and enhance virulence, and they highlight OdsA as a promising target for therapeutic intervention to prevent sepsis in burn patients.

Burn injuries put patients at high risk for severe infections, and Pseudomonas aeruginosa is one of the most dangerous bacteria involved. These infections often spread quickly from the wound to internal organs, leading to life-threatening sepsis. We wanted to understand why P. aeruginosa becomes so aggressive in burn wounds. Our research shows that burn injuries release oleic acid, a fatty acid normally stored in tissues. The bacteria sense this molecule and use it to activate a special communication system called ODS, which changes their behavior and makes them more invasive. When ODS is active, the bacteria penetrate deeper into tissue and spread throughout the body. We also discovered that blocking ODS, either by vaccinating against one of its key enzymes or by using a small-molecule inhibitor, can protect against deadly infections in mice. These findings reveal a new way that P. aeruginosa exploits burn injuries and point to ODS as a promising target for future therapies to improve outcomes for burn patients.