UCLA researchers in the Department of Anesthesiology & Perioperative Medicine have developed a novel therapeutic approach using human extracellular vesicles (EVs) to block harmful effects of bacterial outer membrane vesicles (OMVs) in Pseudomonas aeruginosa pneumonia. This strategy aims to reduce inflammation, disrupt bacterial communication, and improve lung function in severe infections where antibiotics alone may not be effective.
BACKGROUND: Pseudomonas aeruginosa (PA) is a leading cause of hospital-acquired pneumonia and a major driver of acute respiratory distress syndrome (ARDS) in critically ill patients. This gram-negative pathogen has a remarkable ability to resist antibiotics through a combination of membrane impermeability, efflux systems, and β-lactamase enzymes. Despite targeted antimicrobial therapy, mortality from PA-induced ARDS remains high. A key contributor to PA’s virulence is its release of outer membrane vesicles (OMVs)—nanometer-scale lipid vesicles that carry toxic proteins and bacterial signals capable of disrupting host cell function and triggering intense inflammation.
PA tightly regulates OMV production through quorum sensing, a bacterial communication system that enables coordinated responses to environmental stress, including antibiotic exposure and host immune activity. These OMVs can deliver virulence factors directly into host cells leading to host cell death and promote biofilm formation, which further protects bacteria from both immune clearance and antibiotic penetration. There is currently no approved therapy that directly targets OMVs or quorum sensing, representing a critical gap in treatment options for drug-resistant PA pneumonia and ARDS.
INNOVATION: UCLA researchers led by Dr. Jae Woo Lee have developed a novel, host-directed therapeutic strategy using human extracellular vesicles (EVs) to counteract the pathological effects of Pseudomonas aeruginosa outer membrane vesicles (OMVs). These EVs—naturally released by immune cells or found in human plasma—express immune recognition receptors such as CD14 that may enable them to bind bacterial components like lipopolysaccharide (LPS) on OMVs. In preclinical studies, EVs have demonstrated the ability to reduce OMV uptake by human macrophages and improve key physiological outcomes in ex vivo human lung models of bacterial pneumonia.
These findings suggest that EVs may be able to neutralize OMVs by blocking their interaction with host cells and potentially interfering with OMV-associated virulence and quorum sensing activity. By sequestering OMVs, EVs may limit downstream inflammation and tissue injury, offering a new, non-antibiotic approach to treating PA pneumonia and ARDS. The platform is designed for scalability, with therapeutic EVs isolated from sources such as cryo-poor plasma or uninjured lung perfusate—making clinical translation highly feasible.
POTENTIAL APPLICATIONS:
- Adjuvant therapy for multidrug-resistant PA pneumonia
- Suppression of bacterial quorum sensing
- Broad host-directed immunotherapy against bacterial infections
ADVANTAGES:
- Targets pathogen virulence factors independent of antibiotic susceptibility
- Compatible with antibiotics to enhance treatment efficacy
- Derived from patient plasma products, supporting translational feasibility
DEVELOPMENT-TO-DATE: Therapeutic EVs were evaluated in a human ex vivo lung perfusion model, a clinically relevant platform that mimics lung physiology. EVs derived from uninjured lung perfusate or cryo-poor plasma significantly improved outcomes in PA-induced lung injury, including reduced neutrophil influx, improved alveolar fluid clearance, and decreased bacterial burden within six hours of treatment.
In parallel, in vitro studies using human macrophage cell lines demonstrated that EVs reduced uptake of PA-derived OMVs, suggesting a potential neutralizing or decoy effect. Additional experiments with liver-derived cells support the hypothesis that EV–OMV complexes may be more efficiently cleared. Mechanistic observations indicate that bacterial stress and OMV composition are altered by immune stimuli, and EV binding appears to involve CD14. Collectively, these findings support the feasibility and therapeutic promise of EV-based approaches to modulate bacterial virulence and lung injury.
KEYWORDS: Acute respiratory distress syndrome, pseudomonas aeruginosa, extracellular vesicles, bacterial outer membrane vesicles, quorum sensing, innate immunity, biofilm suppression, antibiotic resistance, plasma-derived extracellular vesicles, antibiotic resistance, adjuvant therapy