Reestablishing the lung microbiome : preclinical evaluation of targeted probiotics for pneumonia treatment

Objective

"Nosocomial pneumonia is the second most common and most frequently fatal hospital-acquired infection worldwide. Previous understanding of lung health depicted a dichotomous view of microbial status (sterile vs. infected), leading to ""one-size-fits-all"" treatments that primarily target pathogens but neglect the complex host-microbiome interaction. The RESTORE hypothesis is that re-establishing the healthy respiratory microbiome core using a probiotic composed of lung-specific commensal bacteria and/or their derived metabolites can mitigate pneumonia severity by modulating pathogens and mucosal immunity. My main objectives are: 1) define lung-specific bacterial consortium and their derived metabolites/peptides, whose elimination is associated with pneumonia severity; 2) test their effects in vitro on commensal bacteria and pathogens; and 3) evaluate their impact on pathogens multiplication, microbiome composition, and lung mucosal immunity. I will use data from existing cohorts to identify bacterial consortia with pneumonia severity and integrate multi-omics data to characterize these consortia and their metabolic products. Then, I will assess the interactions within the bacterial consortium and their effects on pathogens by analyzing the growth and transcriptional responses. Finally, I will investigate their therapeutic potential in pneumonia mice models, focusing on pathogen burden, microbiome composition, transcriptomic activity, and immune modulation using single-cell RNA sequencing and flow cytometry. RESTORE represents a pioneering approach by leveraging the lung microbiome to develop non-antibiotic, lung-specific strategies, addressing the complexity of pneumonia pathophysiology beyond pathogen eradication. By employing a multi-disciplinary integration of cutting-edge methodologies, this project could revolutionize pneumonia treatment and potentially extend to other infectious diseases."