Descrizione del progetto
Scoprire gli eventi molecolari che provocano lo sviluppo della malattia dei legionari
L’invecchiamento della popolazione e l’uso crescente di immunomodulatori determinano un’incidenza crescente di infezioni opportunistiche. Il batterio della legionella, in paricolare la Legionella pneumophila, provoca infezioni respiratorie, con una sintomatologia che va dall’influenza lieve alla polmonite grave, che rientrano nella definizione di malattia dei legionari. I meccanismi molecolari della vulnerabilità alla malattia sono scarsamente noti. Al fine di combattere la malattia, il progetto OPTIMISE, finanziato dall’UE, intende impiegare sezioni di tessuto umano tagliate con precisione e polmoni umani interi irrorati come modelli di infezione per lo studio della legionella. Esaminerà la rilevanza clinica dei modelli, analizzerà le risposte trascrizionali delle cellule nei tessuti umani infetti e impiegherà l’istologia e la microscopia d’avanguardia per rilevare le dinamiche e le risposte dell’ospite.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
BT7 1NN Belfast
Regno Unito