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

Descripción del proyecto

Restaurar el microbioma pulmonar para tratar la neumonía

Cada vez hay más pruebas de que, al igual que el intestino, los pulmones sanos también contienen su propio microbioma, una comunidad diversa de microbios comensales que favorece la salud respiratoria y la función inmunitaria. Dado que los pulmones están constantemente expuestos a microbios en el aire y en el tracto respiratorio superior, esto es de esperar. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto RESTORE se centra en la neumonía adquirida en hospitales y propone restablecer el equilibrio microbiano en los pulmones como forma de tratar y prevenir la neumonía con mayor eficacia. Los investigadores probarán probióticos y metabolitos microbianos específicos del pulmón para identificar microbios que podrían reconstruir el microbioma pulmonar. A largo plazo, esto significará un menor uso de antibióticos para el tratamiento de la neumonía.

Objetivo

"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."