The study on co-culture models using human organoids derived from upper airway tissues provides groundbreaking insights on the interaction between Pseudomonas aeruginosa and epithelial cells, especially for patients suffering from cystic fibrosis (CF).
Known for its high antibiotic resistance, P. aeruginosa is notorious for chronic infections, particularly within the airways of individuals with CF, which is caused by mutations affecting the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The disease leads to severe mucosal blockage, creating optimal conditions for P. aeruginosa proliferation and persistence.
The research team, led by C. Pleguezuelos-Manzano and colleagues at the Hubrecht Institute, pioneered a novel 2D co-culture method, utilizing upper airway organoids derived from both healthy and CF individuals. Their approach facilitates the examination of the bacterium-host interactions by employing dual RNA sequencing, which allowed researchers to capture and analyze the gene expression profiles of both the bacteria and the human cells during early infection.
According to the findings published recently, P. aeruginosa was observed to induce inflammation within the epithelial cells, yet interestingly, quorum sensing (a method bacteria use to communicate with each other) did not significantly alter the epithelial response.
“P. aeruginosa induced epithelial inflammation, whereas QS signaling did not affect the epithelial airway cells,” the authors stated, indicating nuances in the bacterial strategies employed during infection.
This study strengthens the need for developing models faithful to the infection scenarios seen within human patients and underlines the importance of investigating how specific bacterial signals influence host responses.
The innovative dual RNA-sequencing approach also revealed significant metabolic rearrangements within P. aeruginosa, coinciding with the environmental conditions provided by the presence of human epithelial cells. The research demonstrated localized oxygen depletion resulting from both high bacterial density and oxygen consumption by the epithelial cells: “This suggests local anoxia due to the oxygen consumption by the epithelium and high-density bacterial population,” the authors explained.
These findings not only illuminate the complex relationship between P. aeruginosa and airway epithelium but also contribute to our fundamental comprehension of pathogenesis during initial stages of infection.
Importantly, previous models used to investigate these interactions typically lacked the relevant human epithelial architecture and biological fidelity found within the new airway organoid model developed. “Our model captures major infection traits from both bacteria and epithelium, including bacterial metabolism, expression of virulence factors, and the induction of an inflammatory response,” noted the authors.
Crucially, this research could inform therapeutic strategies aimed at countering persistent infections. With antibiotic resistance soaring, alternative approaches to treatment must be considered, especially for those afflicted with CF where chronic infections are prevalent.
This advancement builds upon existing methodologies and creates opportunities for future studies to explore how diverse bacterial and host cell factors interplay, potentially guiding the development of therapies aimed at mitigating the impacts of such infections.
The authors call for expanded exploration of co-culture models to resemble human biofilms more closely, combining not only epithelial cells but also immune elements to understand more comprehensively the interactions at play during infections.
Through this innovative approach, researchers intend to pave the way for improved treatments for the many patients impacted by Pseudomonas aeruginosa infections, where every step toward unraveling this complexity brings hope closer to reality.