Description du projet
Comprendre les événements moléculaires menant au développement de la maladie du légionnaire
Le vieillissement de la population et l’utilisation croissante d’immunomodulateurs entraînent une augmentation de l’incidence des infections opportunistes. La bactérie Legionella pneumophila est à l’origine d’infections respiratoires dont les symptômes vont de la grippe légère à la pneumonie grave (communément appelée maladie du légionnaire). Les mécanismes moléculaires expliquant la sensibilité à cette maladie restent méconnus. Pour remédier à cette lacune, le projet OPTIMISE, financé par l’UE, entend créer des modèles d’infection par Legionella sous la forme de lamelles de tissu pulmonaire humain découpées avec précision et de poumons humains entiers perfusés. L’équipe examinera ensuite la pertinence clinique de ces modèles, analysera les réponses transcriptionnelles des cellules dans les tissus humains infectés et s’appuiera sur l’histologie et la microscopie de pointe pour visualiser la dynamique de l’infection et les réponses de l’hôte.
Objectif
Aging populations and the increasing use of immune modulatory medical treatments have given rise to a growing incidence of opportunistic infections. Legionella species are Gram-negative environmental bacteria, which after accidental inhalation can cause respiratory infections with symptoms reaching from a mild flu to a severe pneumonia, called Legionnaires’ disease. Disease progression, i.e. clearance or exacerbation of infection, is determined by the immune status of the host and acute pneumonia usually associated with immune suppression and/or underlying pulmonary conditions, but the molecular mechanisms enhancing susceptibility are poorly understood.
The infection biology of Legionella has been studied mostly in cellular infection models and mice, which do not develop human-like disease. As patients typically present only at late stages of infection, it is unclear to which extent findings from these models reflect the early processes which occur in the human lung during infection and how these drive the clinical outcomes. Similarly, these models fail to explain, why L. pneumophila serogroup 1 strains are the predominant cause of more than 90% of Legionnaires’ disease cases.
In this project I, the applicant Dr. Flavia Viana, will tackle these knowledge gaps by establishing and using human precision cut lung tissue slices (hPCLS) and excorporeal perfused whole human lungs (Ex vivo lung perfusion (EVLP)) as infection models for Legionella. I will determine if and how virulence of different Legionella isolates in these models correlates with their relevance in the clinical practice, analyse the transcriptional responses of all cell types in the infected human tissue using single cell transcriptomics and employ histology, state-of-the-art confocal and light sheet live microscopy, to visualise infection dynamics and host responses, providing unprecedented insight into the molecular events leading to the development of Legionnaires’ disease.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
BT7 1NN Belfast
Royaume-Uni