“Pseudomonas aeruginosa faces fitness trade-offs at the airway mucosal surface"

Host: Dr Megan Bergkessel 

Venue: MSI Small Lecture Theatre, SLS

Abstract 

The opportunistic pathogen Pseudomonas aeruginosa causes severe acute and chronic infections in immunocompromised patients. Due to its resilience to antibiotic treatment, P. aeruginosa infections are a major cause of hospitalization with high mortality rates. Despite an urgent need for novel therapeutic approaches, key aspects of its physiology, including its growth and survival at the airway mucosal surface, remain poorly understood. 

In this talk, I will demonstrate how combining functional genomics (Tn-seq) with tissue-engineered organoids can generate a mechanistic understanding of P. aeruginosa infections and identify new therapeutic targets. Using this approach, we identified selective pressures and adaptation strategies employed by P. aeruginosa to grow and survive antibiotic treatment on the mucosal surface. We first found that metabolic flexibility is a major factor enabling initial colonization. Through genome-scale metabolic models and in silico gene essentiality analyses, we identified specific catabolic and anabolic pathways critical for mucosal colonization. Beyond metabolism, biofilm formation emerged as a key colonization strategy, albeit with significant trade-offs. Testing these predictions with live imaging of infections at the organoid mucosal surface revealed that, while biofilms enhance antibiotic tolerance and select for strains with elevated cyclic-di-GMP, they also impose costs by limiting nutrient access, slowing growth, and reducing virulence. Furthermore, in co-infections, less virulent biofilm-forming strains can protect more virulent non-biofilm strains, suggesting a potential mechanism by which virulent strains persist in the airway during chronic infections. Overall, our findings illustrate how P. aeruginosabalances the competing demands of survival, growth, and virulence in the complex airway environment. These trade-offs likely play a crucial role in driving phenotypic diversity during chronic infections. The mechanisms we uncovered may help explain how virulent strains persist in the airway and contribute to tissue damage and acute exacerbations.  

Finally, because chronic lung infections reshape the airway through cycles of damage and regeneration, I will conclude by discussing how organoid infection models can serve as tractable systems to investigate the airway mucosal epithelium’s response to prolonged exposure to bacteria. These insights could help us understand the long-term physiological impacts on both the host and pathogen during the progression of chronic lung diseases. 

Bio 

Lucas A. Meirelles is an EMBO Postdoctoral Fellow in Alex Persat’s lab at the Swiss Federal Institute of Technology Lausanne (EPFL). His research focuses on host-pathogen interactions in chronic lung infections, using multidisciplinary approaches, including human lung organoids. 

Originally from Brazil, Lucas began his scientific career studying social insects and their parasitic microbes at São Paulo State University and later at the University of Texas at Austin. He earned his PhD at Caltech under the mentorship of Dianne Newman, where he investigated the diverse effects of bacterial secondary metabolites on the physiology of opportunistic pathogens associated with chronic lung infections.